Bicyclo[3.3.0]octenylaldehyde derivatives

ABSTRACT

Bicyclo[3.3.0]octenylaldehyde derivatives represented by the formula: ##STR1## wherein R 1  is a substituent selected from the group consisting of a hydrogen atom and a protective group of a hydroxy group; 
     R 2  is a substituent selected from the group consisting of --CH 2  OR 5 , ##STR2##  where R 5  is a substituent selected from the group consisting of a hydrogen atom and a protective group of a hydroxy group, 
     R 6  is a substituent selected from the group consisting of an alkyl group, an alkenyl group and an alkynyl group, said substituent being straight, branched or cyclic and having 5 to 10 carbon atoms, 
     X is a substituent selected from the group consisting of a vinylene group and an acetylene group, and 
     R 7  is a substituent selected from the group consisting of an alkyl, an alkenyl group, and an alkynyl group, said substituent being straight, branched or cyclic and having 5 to 10 carbon atoms; and 
     R 4  is a hydrogen atom, 
     and a process for producing the derivatives are available for producing a 9(0)-methano-Δ 6 (9.α) -PGI 1 .

BACKGROUND OF THE INVENTION

This invention relates to a bicyclo[3.3.0]octane derivative and aprocess for producing the same.

9(0)-methano-Δ⁶(9α) -PGI₁ has a potent platelet aggregation inhibitingaction. For example, its action is comparable to chemically unstablePGI₂, when human platelet is employed, and it is a compound which can beutilized as a therapeutic or preventive for various diseases ofcirculatory organs (see the test examples shown below).

In the prior art, as the process for producing 9(0)-methano-Δ⁶(9α)-PGI₁, there have been known (a) the process in which it is producedthrough the 14 steps using PGE₂ as the starting material [PreliminaryText for Lectures in 103rd Annual Meeting in Pharmaceutical Society ofJapan, p. 156, (1983)] and (b) the process in which it is produced from1,3-cyclooctadiene through 19 steps [Preliminary Text for Lectures in103rd Annual Meeting in Pharmaceutical Society of Japan, p. 157,(1983)]. The former process has the drawback that the starting materialis expensive, while the latter process that the desired product isformed as a racemic mixture. Further, both processes (a) and (b) arealso disadvantageously very low in the overall yield.

On the other hand,(4'-alkoxycarbonyl-1'-alkenyl)-cis-bicyclo[3.3.0]octene derivative canbe led to 9(0)-methano-Δ⁶(9α) -PGI₁ and its various derivatives byhighly selective reduction of the double bonds of the α-chains,elimination of the protective group for hydroxyl group and hydrolysis ofthe ester.

Further, (4'-alkoxycarbonyl-1'-alkenyl)-cis-bicyclo[3.3.0]octenederivative can easily be led to various carbacyclines stereospecificallyby 1,4-reduction of conjugated diene.

The above carbacyclines are synthesized according to any of theprocesses by the Wittig reaction to cis-bicyclo[3.3.0]octane-3-onederivatives [e.g. W. Skuballa and H. Vorbruggen, Angew. Chem. Int. Ed.Engl., 20, 1046 (1981); W. Skuballa et al. (Schering AG), Eur. Pat. 11,591; Ger. Offen. 2,845,770.7; '83 Inflammation Seminar-ProstaglandinProgram Preliminary Text, Shinsaku Kobayashi, at p. 37].

However, according to this process, a mixture of 5-E derivative [a] and5-Z derivative [b] is obtained, and separation of the 5-E derivative [a]which is useful as pharmaceutical remains as the great problem in thesynthetic process. ##STR3##

SUMMARY OF THE INVENTION

The present inventors have studied extensively to produce9(0)-methano-Δ⁶(9α) -PGI₁ carbacyclines from a cheap starting materialat good yield and with optical activity as well as steric configurationspecificity, and consequently found that the compound of the presentinvention and the process for producing the same can be an importantintermediate and a process for achieving the object to accomplish thepresent invention.

This invention concerns a compound of the formula: ##STR4## wherein R¹ :a hydrogen atom or a protective group of a hydroxy group;

R² : --CH₂ OR⁵, ##STR5## (R⁵ : a hydrogen atom or a protective group ofa hydroxy group, R⁶ : straight, branched or cyclic alkyl group, alkenylgroup or alkynyl group each having 5 to 10 carbon atoms,

X: a vinylene group or an acetylene group,

R⁷ : a straight, branched or cyclic alkyl group, alkenyl group oralkynyl group each having 5 to 10 carbon atoms);

R³ : a formyl group or --Y--(CH₂)₂ --COOR⁸

(R⁸ : a hydrogen atom or an alkyl group, and

Y: a vinylene group or an alkylene group);

R⁴ : a hydroxy group when the compound is an octane derivative, or ahydrogen atom when the compound is an octene derivative;

dotted line: optional presence of a double bond;

provided that where R² is ##STR6## R³ being --(CH₂)₄ --COOR⁸ isexcluded, and a process for producing the same.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The bicyclo[3.3.0]octane derivative represented by the above formula [I]of this invention can be led to(3-oxo-1-alkenyl)-cis-bicyclo[3.3.0]octene derivative by subjecting thebicyclo[3.3.0]octenylaldehyde to the reaction step as hereinafterdescribed or oxidizing the bicyclo[3.3.0]octene derivative and thensubjecting the oxidized product to Wittig reaction. The(3-oxo-1-alkenyl)-cis-bicyclo[3.3.0]octene derivative can be led to9(0)-methano-Δ⁶(9α) -PGI₁ by reducing the ketone, carrying out thedeprotection reaction of the hydroxy group and subjecting the ester tohydrolysis (see Reference example shown below).

The bicyclo[3.3.0]octane derivative represented by the above formula [I]of this invention can be stated to be a very useful intermediate in thatit can be led to not only the natural type ω-chain of prostaglandinskelton but also to a prostaglandin derivative having a nonnatural typeω-chain having higher activity as disclosed in a literature[Casals-Stenzel, J. et al., Protaglandins, Leukotrienes Med. 1983, 10(2), pp. 197-212].

The bicyclo[3.3.0]octane derivative represented by the above formula [I]can be produced according to the reaction schemes as shown below.

The protective group of hydroxy group in this invention may include, forR¹, tetrahydropyranyl group, methoxymethyl group,4-methoxytetrahydropyranyl group, 1-ethoxyethyl group,1-methyl-1-methoxyethyl group, t-butyldimethylsilyl group,diphenyl-t-butylsilyl group, benzoyl group, acetyl group, triethylsilylgroup, etc. and, for R⁵, t-butyldimethylsilyl group, benzoyl group,acetyl group, tetrahydropyranyl group, methoxymethyl group,4-methoxytetrahydropyranyl group, 1-ethoxyethyl group,1-methyl-1-methoxyethyl group, diphenyl-t-butylsilyl group,triethylsilyl group, etc.

The substituent Y in the substituent R³ may preferably include avinylene group and an ethylene group.

In the compounds of the present invention, bicyclo[3.3.0]octenylaldehydederivatives [I'] can be prepared following the reaction schemes shownbelow: ##STR7## wherein R¹ and R⁵ are the same as defined above.

[The first step]

This step produces a hydroxymethyl cyclopentane derivative representedby the above formula [III] by hydration of a cyclopentylidene derivativerepresented by the above formula [II].

The cyclopentylidene derivative represented by the above formula [II] isa compound which can easily be obtained by reducing a Corey's lactonederivative to lactol, which is then subjected to the Wittig reaction tooxidation of the hydroxyl group, followed by the methylenation reaction(see Reference example shown below).

The hydration reaction in this step is conducted out by hydroborationand oxidation. In carrying out hydroboration, there may be employed ahydroborating reagent such as 9-BBN (9-borabicyclo[3.3.1]nonane),thexylborane, disiamylborane, etc. The amount of the hydroborating agentused may be generally 1 to 1.5 equivalent.

The reaction is desired to be carried out in a solvent, preferably anether type solvent such as tetrahydrofuran, diglyme, diethylether, etc.

The reaction proceeds smoothly at -25° C. to room temperature.

Further, this step carries out oxidation of the product subsequent tothe hydroboration without isolation thereof. The oxidation may becarried out by use of an oxidizing agent such as an alkaline hydrogenperoxide, an amine oxide, oxygen, peracid, etc. The amount of theoxidizing agent employed may be 5 to 15 equivalents.

The reaction proceeds smoothly at room temperature to 60° C.

In this step, the compound formed by hydroboration with the use of, forexample, 9-BBN may be estimated to have a formula as shown below:##STR8##

[The second step]

This step produces a β-hydroxyaldehyde derivative represented by theabove formula [IV] by oxidation of the hydroxymethyl cyclopentanederivative represented by the above formula [III].

In carrying out oxidation, it is possible to usedimethylsulfoxide-oxalyl chloride, dimethylsulfoxide-a pyridine complexof sulfur trioxide, etc. The amount of the oxidizing agent employed maybe generally 1 to 5 equivalents.

The reaction is desired to be carried out in a solvent, for example, ahalogenated hydrocarbon such as methylene chloride.

The reaction can proceed smoothly at a temperature, which may differdepending on the oxidizing agent employed, but generally at -70° C. toroom temperature.

For obtaining the oxidized product in this step, a tertiary amine suchas triethylamine, diisopropylamine, etc. is added into the reactionproduct and treatment is carried out at -70° C. to room temperature.Under this condition where dialdehyde is formed, intramolecular aldolcondensation occurs rapidly to give a β-hydroxyaldehyde derivativerepresented by the above formula [IV].

After completion of this step, the product is subjected to the nextthird step without isolation.

[The third step]

This step produces a bicyclo[3.3.0]octenylaldehyde derivativerepresented by the above formula [I'] by dehydrating theβ-hydroxyaldehyde derivative represented by the above formula [IV]obtained in the second step as described above in the presence of anacidic catalyst.

Dehydration is required to be carried out in the presence of an acidiccatalyst. As the acidic catalyst, an acid-ammonium salt is available. Anacid-ammonium salt can be formed from an acid and an amine. The acidavailable may be exemplified by trifluoroacetic acid, toluenesulfonicacid, camphorsulfonic acid, acetic acid, etc. The amine available may beexemplified by dibenzylamine, diethylamine, dimethylamine,diisopropylamine, piperidine, pyrrolidine, piperazine, etc. These acidsand amines may appropriately be selected and combined to be provided foruse. Above all, the catalyst comprising a combination of trifluoroaceticacid and dibenzylamine is preferred on account of good yield of thedesired product. The amount of the catalyst employed may be about 0.2equivalent, but it is preferred to employ about one equivalent in orderto proceed rapidly the reaction.

The reaction is desired to be carried out in a solvent, for example, anaromatic hydrocarbon such as benzene, toluene, xylene, etc.

The reaction temperature may be selected within the range from roomtemperature to 100° C., but preferably within the range from 50° C. to70° C. in order to carry out the reaction smoothly.

The bicyclo[3.3.0]octenylaldehyde derivative obtained as described abovecan be subjected to the steps A to D as described below, whereby ω-chaincan be introduced thereinto. ##STR9## wherein R¹ and R⁵ are the same asdefined above, R⁶ is a straight, branched or cyclic alkyl, alkenyl oralkynyl group each having 5 to 10 carbon atoms, R⁸ is a hydrogen atom oran alkyl group and R⁹ is a phenyl group or an alkyl group.

[Step A]

This step produces an alkenylbicyclo[3.3.0]octene derivative representedby the above formula [VI] by carrying out the reaction between thebicyclo[3.3.0]octenylaldehyde derivative represented by the aboveformula [I'] and 3-carboxypropylphosphonium bromide.

This step is required to be carried out in the presence of a base. Thebase may include potassium t-butoxide, butyl lithium, sodium salt ofdimethylsulfoxide, etc. For carrying out the reaction with goodefficiency, it is preferred to employ potassium t-butoxide. The amountof the base employed may be generally 1 to 1.2 equivalent based on theabove 3-carboxypropylphosphonium bromide.

The reaction may be carried out preferably in an ether solvent such astetrahydrofuran, dimethoxyethane, diethyl ether, etc. The solvent is notparticularly limited, provided that it does not interfere with thereaction.

The reaction temperature may be selected within the range from 0° C. to50° C., at which the reaction can proceed smoothly.

The compound obtained in this step is formed generally as a freecarboxylic acid, but it can be isolated as an ester by use of thecondition of diazomethane or alkylhalide-diazabicycloundecene-acetonitrile for the reactions in thesubsequent step et seq. Conversion to ester may be conducted accordingto the method easily done by those skilled in the art.

[Step B]

This step produces a bicyclo[3.3.0]octene derivative represented by theabove formula [VII] in which only one of the olefins is selectivelyreduced by catalytic reduction of the alkenylbicyclo[3.3.0]octenederivative represented by the formula [VI] obtained in the previous stepA.

The available catalysts include palladium catalysts such aspalladium-carbon, palladium black, etc., Wilkinson catalysts, platinum,nickel, etc. The catalyst may be sufficiently employed in the so-calledcatalytic amount.

In practicing this step, hydrogen may be allowed to react with thecompound under normal pressure or under pressurization.

The reaction may be carried out preferably in a solvent, for example, analcohol solvent such as methanol, ethanol, etc. or an ester solvent suchas ethyl acetate, etc.

The reaction can proceed smoothly at a temperature selected within therange from -25° C. to room temperature.

[Step C]

This step produces a hydroxymethylbicyclo[3.3.0]octene derivativerepresented by the above formula [VIII] by selective deprotection of R⁵of the bicyclo[3.3.0]octene derivative represented by the above formula[VII] obtained in the previous step B.

In carrying out deprotection, when R⁵ is a silyl group,tetra-n-butylammonium fluoride may be used as the deprotecting agent,while potassium carbonate may be used, when it is benzoyl group oracetyl group.

The reaction should desirably be conducted in a solvent. Whentetra-n-butylammonium fluoride is used as the deprotecting agent, anether solvent such as tetrahydrofuran, dimethoxyethane, ethyl ether,etc. may preferably be used. On the other hand, when potassium carbonateis used as the deprotecting agent, an alcohol solvent such as methanol,ethanol, etc. may preferably be used.

The reaction can proceed smoothly at -25° C. to room temperature.

[Step D]

This step produces a (3-oxo-1-alkenyl)-cis-bicyclo[3.3.0]octenederivative represented by the above formula [XI] by oxidizing thehydroxymethylbicyclo[3.3.0]octene derivative represented by the aboveformula [VIII] obtained in the previous step C and subsequently allowingthe resultant product to react with a compound represented by the aboveformula [IX] or the above formula [X].

The oxidation in this step is required to be carried out in the presenceof an oxidizing agent. The oxidizing agent may include Collins reagent,dimethyl sulfoxide-pyridine complex of sulfur trioxide, pyridiniumchlorochromate, dimethyl sulfoxide-oxalyl chloride, etc. The amount ofthe oxidizing agent employed may be 7 to 10 equivalents in the case ofCollins reagent, and 1 to 5 equivalents in the case of other oxidizingagents.

The reaction should desirably be carried out in a solvent, preferably ina halogenated hydrocarbon such as methylene chloride, chloroform, etc.

The reaction can proceed smoothly at a temperature within the range from-70° C. to room temperature.

In this step, the product obtained by oxidation is not isolated butsubsequently subjected to the reaction with a compound represented bythe above formula [IX] or the above formula [X]. The compoundsrepresented by the above formula [IX] include, for example,dimethyl(2-oxoheptyl)phosphonate,dimethyl(2-oxo-3-methylheptyl)phosphonate,dimethyl(2-oxo-3,3-dimethylheptyl)phosphonate,dimethyl(2-oxo-4,8-dimethyl-7-nonenyl)phosphonate,dimethyl(2-oxo-4,4,8-trimethyl-7-nonenyl)phosphonate,dimethyl(2-oxo-2-cyclopentylethyl)phosphonate and the like. Thecompounds represented by the above formula [X] includetributylphosphine-2-oxoheptylidene,tributylphosphine-2-oxo-3-methylheptylidene,tributylphosphine-2-oxo-3,3-dimethylheptylidene,tributylphosphine-2-oxo-4,8-dimethyl-7-nonenylidene,tributylphosphine-2-oxo-4,4,8-trimethyl-7-nonenylidene,tributylphosphine-2-oxo-2-cyclopentylethylidene and the like. When thecompound represented by the above formula [X] is selected as thestarting material, it is preferred to carry out the reaction in thepresence of a base, such as sodium hydride, butyl lithium, potassiumt-butoxide, etc. in order to obtain the desired product at good yield.

The reaction should desirably be conducted in a solvent, e.g. an ethersolvent such as tetrahydrofuran, dimethoxyethane, diethyl ether, etc. oran aromatic solvent such as benzene, toluene, xylene, etc.

The reaction temperature may be within the range from -25° C. to 50° C.when employing a compound represented by the formula [IX] or within therange from 20° C. to 150° C. when employing a compound represented bythe formula [X].

The compound obtained by oxidation in this step may be estimated to be acompound represented by the formula: ##STR10## wherein R¹ is aprotective group for hydroxy group and R⁸ is a hydrogen atom or an alkylgroup.

In the present invention, the (1-alkenyl)-bicyclo[3.3.0]octenylderivative represented by the following formula [I-a]: ##STR11## can beproduced as follows.

That is, in the presence of a base, bicyclo[3.3.0]octenylaldehyderepresented by the formula [I']: ##STR12## wherein R¹ and R⁵ are ahydrogen atom or protective groups a hydroxy group,

is allowed to react with a 3-carboxypropylphosphonium halilderepresented by the formula [XII]: ##STR13## wherein R¹⁰ is an alkylgroup or an aryl group, and

X is a halogen atom,

followed by esterification if desired, to produce a(1-alkenyl)-bicyclo[3.3.0]octene derivative.

The bicyclo[3.3.0]octenylaldehyde derivative represented by the formula[I'] can be synthesized easily from Coley lactone which the typicalintermediate for various prostaglandins (see Reference example shownbelow). In the above formula [I'], R¹ and R⁵ may include hydrogen atom,tetrahydropyranyl group, t-butyldimethylsilyl group, 1-ethoxyethylgroup, diphenyl-t-butylsilyl group, methoxymethyl group,1-methyl-1-methoxyethyl group, 4-methoxytetrahydropyranyl group, methylgroup, benzyl group, benzoyl group, acetyl group, β-methoxyethoxymethylgroup, triethylsilyl group, etc.

The 3-carboxypropylphosphonium halide represented by the above formula[XII] can be prepared from, for example, 4-bromobutanoic acid andtriphenylphosphine [W. Seidel, J. Knolle, and H. J. Schafer, Chem. Ber.,110, 3544 (1977)]. R¹⁰ in the above formula [XII] may be, for example,an alkyl group such as butyl or an aryl group such as a phenyl, and Xmay be chlorine atom, bromine atom or iodine atom.

The present invention is required to be carried out in the presence of abase. Examples of the base may be organic bases such as potassiumt-butoxide, sodium t-amyloxide, sodium methoxide, sodium ethoxide,sodium salt of dimethyl sulfoxide (DMSO), potassium salt of DMSO, butyllithium, sec-butyl lithium, t-butyl lithium, phenyl lithium, sodiumhydride, potassium hydride, lithium diisopropylamide, lithiumdiethylamide, sodium amide and the like, and inorganic bases such assodium hydroxide, potassium hydroxide, potassium carbonate and the like.The amount of the base employed may be sufficiently be 2 to 3 moleequivalents based on the bicyclo[3.3.0]octenylaldehyde derivativerepresented by the above formula [I'].

The present invention should desirably be carried out in a solvent. Thesolvent may be an ether solvent such as tetrahydrofuran,dimethoxyethane, ether, 2-methoxyethyl ether, etc., an aromatic solventsuch as toluene, benzene, etc., or a polar solvent such as DMSO, HMPT,DMF, etc., when employing an organic base; or alternatively a halogenicsolvent such as methylene chloride, chloroform, etc. or a solventmixture of an aromatic solvent such as toluene, benzene, etc. withwater, when employing an inorganic base.

When an inorganic base is employed, the reaction system consists of twolayers. For the purpose of effective action of these bases, it ispreferred to carry out the reaction in the presence of a catalyst forinter-phase migration generally employed for two-layer system reactionsuch as tetramethylammonium bromide, tetrabutylammonium iodide, etc.,whereby the desired product can be obtained with good efficiency. Thereaction can proceed smoothly by selecting a temperature within therange from -78° C. to 100° C. In the present invention, esterificationmay be conducted, if desired.

It is possible to derive an alkyl ester of the compound represented bythe above formula [I-a] wherein R⁸ represents a hydrogen atom. That is,the compound obtained by the above reaction may be allowed to react withdiazomethane in an ether solvent to be quantitatively converted into amethyl ester derivative, which can in turn be allowed to react withvarious alkyl halides such as ethyl bromide, propyl bromide, butylbromide, etc. in acetonitrile in the presence of1,8-diazabicyclo[5,4,0]undecene (DBU) to be converted to correspondingethyl ester, propyl ester and butyl ester derivatives, respectively. Thereaction can proceed smoothly by selecting a temperature within therange from -25° C. to 100° C.

In the present invention, the(4'-alkoxycarbonyl-1'-alkenyl)-cis-bicyclo[3.3.0]octene derivativerepresented by the following formula [I-b]: ##STR14## can be producedaccording to the following steps: ##STR15## wherein R¹, R⁵, R⁷, and R⁸are the same as defined above.

[The first step]

This step produces a hydroxymethyl derivative [VIII] by selectiveelimination of the protective group for the primary hydroxy group of aconjugated diene derivative represented by the above formula [VI'].Deprotection of this step is carried out with fluoride ions when thesilyl group is protected, and tetrabutylammonium fluoride, potassiumfluoride, etc. may be used. This step should desirably be conducted in asolvent, preferably an ether solvent such as tetrahydrofuran. In thisstep, the reaction can proceed smoothly at a temperature within therange from -25° C. to 100° C.

[The second step]

This step produces an α,β-unsaturated ketone by oxidizing thehydroxymethyl derivative represented by the formula [VIII] obtained inthe first step, and then allowing the resultant product with a compoundrepresented by the above formula ]IX].

This step can be carried out under the same conditions in the step D forintroducing ω-chain into the bicyclo[3.3.0]octenylaldehyde derivative asdescribed above. The compounds represented by the above formula [IX] mayinclude, for example, dimethyl(2-oxo-3-methyl-5-heptynyl)phosphonate,dimethyl(2-oxo-4(R)-methyl-8-methyl-7-nonenyl)phosphonate and the like.This step may preferably be conducted in the presence of a base forobtaining the desired compound with good efficiency. For example, a basesuch as sodium hydride, potassium hydride, butyl lithium, potassiumt-butoxide, etc. may be employed.

The compound obtained by oxidation in this step may be estimated to be acompound represented by the formula: ##STR16##

[The third step]

This step produces an allyl alcohol derivative by reduction of thecarbonyl group of the α,β-unsatuated ketone represented by the aboveformula [XI'] obtained in the second step. Reduction in this step isrequired to be carried out in the presence of a reducing agent. Thereducing agent may include sodium borohydride,diisobutylaluminum-2,6-di-t-butyl-4-methyl-phenoxide, etc. The amount ofthe reducing agent used may be 1 to 15 equivalents. The reaction shoulddesirably be carried out in a solvent, e.g. an alcohol solvent such asmethanol, ethanol and the like, an aromatic hydrocarbon solvent such asbenzene, toluene, etc. The reaction can proceed smoothly at atemperature in the range from -78° C. to room temperature. The allylalcohol derivative obtained in this step is a mixture of α-isomer andβ-isomer.

[The fourth step]

This step produces a diol derivative by elimination of the protectivegroup of the secondary hydroxyl group of the allyl alcohol derivativerepresented by the formula [I-c] obtained in the third step.Deprotection in this step is carried out in the presence of an acid. Theacid to be employed may be acetic acid, pyridinium salt of p-toluenesulfonic acid, etc. The reaction should desirably be conducted in asolvent such as THF-water, ethanol-water, etc. The reaction can proceedsmoothly at room temperature to 100° C. The diol derivative obtained inthis step can be easily separated into isomers at the 15-position(prostaglandin numbering) into a highly polar isomer 15α and a lowlypolar isomer 15β.

[The fifth step]

This step protects the two hydroxy groups of the diol derivativerepresented by the above formula [I-d] obtained in the fourth step, ifdesired. The protective group to be employed may be, for example,t-butyldimethylsilyl group, triethylsilyl group, tetrahydropyranylgroup, 1-ethoxyethyl group, diphenyl-t-butylsilyl group,1-methyl-1-methoxyethyl group, etc. It is desired to employ thecondition of t-butyldimethylsilylchloride-imidazole-DMF in the case oft-butyldimethylsilyl group; of triethylsilyl chloride-pyridine in thecase of triethylsilyl group; of dihydropyrane-catalytic amount ofp-toluene sulfonic acid-methylene chloride in the case oftetrahydropyranyl group; of ethyl vinyl ether-catalytic amount ofp-toluene sulfonic acid-methylene chloride in the case of 1-ethoxyethylgroup; etc.

The reaction can proceed readily at 0° C. to 100° C.

The (4'-alkoxycarbonyl-1'-alkenyl)-cis-bicyclo[3.3.0]octene derivativeof the present invention has an asymmetric carbon in the molecule, andthe present invention is inclusive of the R-configuration or theS-configuration or a mixture of those at any desired ratio.

In the present invention, a bicyclo[3.3.0]octane derivative representedby the following formula [I-e]: ##STR17## can be further producedaccording to the following steps: ##STR18## wherein R¹, R⁵ and R⁸ arethe same as defined above.

[The first step]

This step produces a cyclopentylidene derivative represented by theformula [XIV] by methylenation of the cyclopentanone derivativerepresented by the above formula [XIII].

The cyclopentanone derivative represented by the above formula [XIII] isa compound which can be obtained easily by reducing a Coley lactonederivative into a lactol, subjecting the lactol to the Wittig reaction,converting the carboxyl group into ester group and oxidizing the hydroxygroup (see Reference examples shown below).

The group R⁸ in the formula [XIII] may be, for example, an alkyl groupsuch as methyl, ethyl, etc.

The methylenation in this step may be carried out by use of a mixedreagent of methylene bromide-titanium tetrachloride-zinc [L. Lombardo,Tetrahedron Lett., 23, 4293 (1982)] or Johnson reagent [C. R. Johnson,J. R. Shanklin, R. A. Kirchoff, J. Am. Chem. Soc., 95, 6462 (1973)]. Thereaction should desirably be carried out in a solvent, for example, asolvent mixture such as a halogenic solvent (e.g. methylenechloride)--an ether solvent (e.g. tetrahydrofuran) in the case of usingthe former reagent, while an ether solvent in the case of the latterreagent. The reaction can proceed smoothly at -80° C. to 60° C., butroom temperature is preferred because the reaction can be carried outwithout heating or cooling.

When the protective group R¹ in the cyclopentylidene derivative issubjected to subsequent steps, particularly the fourth step, it ispreferably converted to a protective group which is high in thermalstability, such as t-butyldimethylsilyl group, diphenyl-t-butylsilylgroup, methyl group, etc.

[The second step]

This step can be carried out according to the same procedure as in thefirst step in preparation of the bicyclo[3.3.0]octenylaldehydederivative as described above.

Further, as described above, this step oxidizes the product withoutisolation subsequent to hydroboration. In oxidation, an oxidizing agentselected from peroxides of hydrogen peroxide, peracetic acid, perbenzoicacid, etc. may be employed. When a peroxide is employed as the oxidizingagent, the peroxide is desired to be in a basic state and a base such ascaustic soda may be employed for this purpose. The amount of theoxidizing agent to be employed may be generally 5 to 15 equivalents. Thereaction can proceed smoothly at -20° to 60° C., but the reaction atroom temperature is preferable because of simple operation.

[The third step]

This step produces a formylcyclopentane derivative represented by theabove formula [XVI] by oxidation of the hydroxymethylcyclopentanederivative represented by the above formula [XV] obtained in the secondstep.

In carrying out oxidation, it is possible to use an oxidizing agent suchas pyridinium chlorochromate (PCC) in the presence of sodium acetate,Collins reagent, pyridinium dichromate (PDC), dimethyl sulfoxide(DMSO)-pyridinium complex of sulfur trioxide, DMSO-oxalyl chloride, etc.The amount of the oxidizing agent employed is different depending on theoxidizing agent, but generally 1 to 8 equivalent.

The reaction should desirably be conducted in a solvent, for example, ahalogenic solvent such as methylene chloride, chloroform, etc. Thereaction temperature is different depending on the oxidizing agentemployed. When PCC, Collins reagent, PDC or DMSO-pyridinium complex ofsulfur trioxide is employed, the reaction can proceed readily at -20° C.to 30° C. In the case of DMSO-oxalyl chloride, the reaction can proceedsmoothly at -70° C. to room temperature.

[The fourth step]

This step produces an alkenylbicyclo[3.3.0]octane derivative representedby the above formula [I-a] by treating the formylcyclopentane derivativerepresented by the above formula [XVI] obtained in the third step underheating.

This step is the so-called thermal heteroene reaction and the heatingcondition may be selected within the range of from 120° to 300° C.However, for carrying out the reaction efficiently, the range from 150°to 250° C. is preferred.

The reaction should desirably be conducted in a solvent, for example, anaromatic hydrocarbon such as benzene, toluene, xylene and the like.

[The fifth step]

This step produces an alkylbicyclo[3.3.0]octane derivative representedby the above formula [I-g] by catalytic reduction of thealkenylbicyclo[3.3.0]octane derivative represented by the above formula[I-f] obtained in the fourth step.

The catalysts available include palladium catalysts such aspalladium-carbon, palladium black, etc., Wilkinson catalyst, platinum,nickel, etc. It is sufficient to employ the catalyst in the so-calledcatalytic amount.

In practicing this step, hydrogen may be allowed to react with thecompound either at normal pressure or under pressurization.

The reaction should desirably be conducted in a solvent, for example, analcohol solvent such as methanol, ethanol, etc. or an ester solvent suchas ethyl acetate.

The reaction can proceed smoothly at a temperature which may be selectedwithin the range from -25° C. to room temperature.

The present invention is described in more detail by referring to thefollowing Reference examples and Examples.

REFERENCE EXAMPLE 1

[2-Oxa-3-oxo-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane](2.22 g, 6 mmol) was dissolved in toluene (10 ml) under argon gasatmosphere, and the solution was cooled to -75° C. To the solution wasadded diisobutylalminum hydride (25 g/100 ml hexane solution; 5.1 ml, 9mmol) and the mixture was stirred at -75° C. for 70 minutes. Methanolwas added at -75° C. until generation of hydrogen had not been admittedand the temperature of the mixture was raised to room temperature. Afterthe mixture was diluted with ethyl acetate (130 ml), washed with asaturated saline solution (20 ml×4 times). The mixture was dried withanhydrous magnesium sulfate, distilled out the solvents to obtain[l-2-oxa-3-hydroxy-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]-octane](2.33 g, Yield: 100%).

IR (neat): 3430, 2950, 2860, 835 cm⁻¹.

NMR δ (CDCl₃): 5.70-5.30 (m, 1H), 4.85-4.55 (m, 2H), 4.40-3.25 (m, 5H),0.90 (s, 9H).

Mass m/z (%): 213 (5), 159 (17), 85 (100), 75 (19), 73 (13).

[α]_(D) ²⁰ =-28° (c=1.98, MeOH).

REFERENCE EXAMPLE 2

Potassium t-butoxide (3.16 g, 28.2 mmol) was dissolved in THF (50 ml)under argon gas atmosphere. To the solution was added at roomtemperature methyltriphenylphosphonium bromide (10.07 g, 28.2 mmol)which was previously dried enough at 100° C. under reduced pressure.After 5 minutes stirring, to the mixture was added[l-2-oxa-3-hydroxy-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane(3.40 g, 9.1 mmol) in THF solution (30 ml) and the mixture was stirredat room temperature for 20 minutes. After a saturated aqueous ammoniumchloride solution was added the mixture, THF was distilled out therefromunder reduced pressure. The resultant aqueous layer was extracted withether and the extract was washed with a saturated saline solution. Afterdryness with anhydrous magnesium sulfate, ether was distilled out. Theresidue was purified through silica gel column chromatography(ether:n-hexane=2:3) to obtain[d-2α-allyl-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1α-cyclopentanol](3.18 g, 94%).

IR (neat): 3500, 2950, 2870, 1640, 835 cm⁻¹.

NMR δ (CDCl₃): 5.80 (m, 1H), 5.00 (m, 2H), 4.65 (bs, 1H), 4.30-3.00 (m,6H), 0.90 (s, 9H).

Mass m/z (%): 285 (1), 229 (1), 211 (3), 159 (26), 85 (100), 75 (21), 73(13).

[α]_(D) ²⁰ =+21° (c=2.44, MeOH).

REFERENCE EXAMPLE 3

To methylene chloride (40 ml) was dissolved[d-2α-allyl-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1α-cyclopentanol](3.16 g, 8.5 mmol) and then sodium acetate (280 mg, 2.6 mmol) and Celite(3.36 g) were added thereto. To the resultant mixture was added, underargon gas atmosphere at 0° C., pyridinium chlorochromate (3.68 g, 17.1mmol) and stirred at 0° C. for 18 hours. The reaction mixture wasdiluted with ether and purified through florisil column chromatography(ether:n-hexane=1:3 to 3:1) to obtain[l-2α-allyl-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentanone](2.82 g, Yield: 90%).

IR (neat): 2950, 2880, 1748, 1642, 840 cm⁻¹.

NMR δ (CDCl₃): 5.70 (m, 1H), 5.03 (d, J=17 Hz, 1H), 5.00 (d, J=11 Hz,1H), 4.65 (bs, 1H), 4.30 (m, 1H), 3.30-4.00 (m, 4H), 0.90 (s, 9H).

Mass m/z (%): 209 (17), 159 (17), 85 (100), 75 (35), 73 (23), 41 (17).

[α]_(D).sup.° =-55° (c=2.19, MeOH).

REFERENCE EXAMPLE 4

[l-2α-allyl-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentanone](2.79 g, 7.57 mmol) was dissolved in methylene chloride (26 ml) and tothe solution was added a zinc-titanium chloride-methylene bromidereagent (Zn--TiCl₄ --CH₂ Br₂ /THF, 46 ml) at room temperature. Afterdisappearance of the starting materials had been confirmed by using TLC,the reaction mixture was poured into a mixed solution of saturatedaqueous sodium hydrogencarbonate solution (500 ml) and ether (500 ml).After the ether layer was separated from the mixture, the aqueous layerwas further extracted with ether. The ether layers were combined, andthe mixture was washed with a saturated saline solution, dried overanhydrous magnesium sulfate and evaporated out the solvents. The residuewas purified through silica gel column chromatography(ether:n-hexane=1:10) to obtain[l-2α-allyl-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentylidene](2.48 g, Yield: 90%).

IR (neat: 2950, 2870, 1660, 1640, 835 cm⁻¹.

NMR δ (CDCl₃): 5.60 (m, 1H), 4.75-5.20 (m, 4H), 4.63 (bs, 1H), 3.30-4.30(m, 5H), 0.90 (s, 9H).

Mass m/z (%): 159 (18), 133 (11), 85 (100), 75 (19), 73 (13).

[α]_(D) ²⁰ =-43° (c=2.84, MeOH).

REFERENCE EXAMPLE 5

9-Borabicyclo[3.3.0]nonane (dimer, 2.472 g, 20.3 mmol) was suspended inTHF (28 ml) under argon gas atmosphere. A solution of[l-2α-allyl-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentylidene](2.476 g, 6.75 mmol) dissolved in THF (45 ml) was added dropwise to theaforesaid suspension under ice-cooling, the mixture was stirred at 5° to10° C. for 7.5 hours. To the mixture were added a 6N aqueous sodiumhydroxide solution (13.5 ml, 81 mmol) and a 30% aqueous hydroperoxidesolution (11.5 ml, 101.3 mmol) and stirred at 60° C. for 1.5 hours.After evaporation of THF under reduced pressure, the resultant mixturewas extracted with ethyl acetate. The separated organic layer was washedsuccessively with an aqueous sodium thiosulfate solution and a saturatedsaline solution. The thus treated mixture was dried over anhydrousmagnesium sulfate and then distilled out the solvents. The residue waspurified through silica gel column chromatography (ether:methanol= 40:1)to obtain[d-1α-hydroxymethyl-2α-(3-hydroxypropyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentane](2.65 g, Yield: 97%).

IR (neat: 3400, 2940, 2860, 835 cm⁻¹.

NMR δ (CDCl₃): 4.65 (bs, 1H), 4.10 (m, 1H), 3.15-3.95 (m, 8H), 0.90 (s,9H).

Mass m/z (%): 159 (19), 149 (18), 133 (19), 121 (13), 105 (15), 93 (10),91 (10), 85 (100), 79 (11), 75 (34), 73 (18), 67 (17), 57 (24), 55 (16),43 (17), 41 (21).

[α]_(D) ²⁰ =+2° (c=1.65, MeOH).

REFERENCE EXAMPLE 6

In the method as described in Reference examples 1 to 5, the sameprocedures were carried out as in Reference examples 1 to 5 except that[2-oxa-3-oxo-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane(1.11 g, 3.88 mmol) was employed as the starting material to yield[1α-hydroxymethyl-2α-(3-hydroxypropyl)-3β-(1-methyl-1-methoxyethyloxymethyl)-4α-tetrahydropyranyloxycyclopentane(1.13 g, Yield: 81%).

IR (neat): 3400, 2940, 2860, 831 cm⁻¹.

NMR δ (CDCl₃): 4.61 (bs, 1H), 3.40-4.20 (m, 9H), 3.20 (s, 3H), 1.34 (s,6H).

Mass m/z (%): 360, 342, 328, 257.

EXAMPLE 1

Oxalyl chloride (1.88 ml, 21.6 mmol) was dissolved in 55 ml of methylenechloride at -60° C. under argon gas atmosphere. To the solution wasadded a solution of dimethyl sulfoxide (3.39 ml, 47.7 mmol) dissolved inmethylene chloride (15 ml). After the mixture was stirred at -60° C. for20 minutes, a solution of[d-1α-hydroxymethyl-2α-(3-hydroxypropyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentane](1.48 g, 3.67 mmol) dissolved in methylene chloride (30 ml) was addedthereto. After the mixture was stirred at -60° C. for 20 minutes,triethylamine (15.36 ml, 110.1 mmol) was added thereto and thetemperature of the mixture was raised to room temperature. Water waspoured into the mixture and the mixture was extracted with methylenechloride. The separated organic layer was washed with an aqueous salinesolution and dried over anhydrous magnesium sulfate. Evaporation of thesolvent to obtain [2-hydroxy-3-formyl-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane](1.19 g, Yield: 81%). According to spectrum data, this compound wasequilibrium compound between β-hydroxyaldehyde and lactol.

IR (KBr): 3450, 2950, 2870, 2750, 1730, 835 cm⁻¹.

NMR δ (CDCl₃): 9.75 (trace), 4.65 (m, 1H), 3.10-4.50 (m, 6H), 0.90 (s,9H).

Mass m/z (%): 313 (trace, M⁺ -85), 159 (15), 85 (100), 75 (17), 73 (12),57 (12), 47 (11).

EXAMPLE 2

[2-Hydroxy-3-formyl-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane](1.19 g, 2.97 mmol) was dissolved in benzene (4.5 ml). To the solutionwas added dimethylammonium trifluoroacetate (1.14 g, 3.66 mmol) underargon gas atmosphere and the mixture was stirred at 50° to 70° C. for 16hours. After the reaction mixture was allowed to stand for cooling,water (50 ml) was added thereto and the mixture was extracted withether. After an ether layer was separated, the ether layer was washedsuccessively with a saturated aqueous ammonium chloride solution, asaturated aqueous sodium hydrogencarbonate solution and water. The etherlayer was dried over anhydrous magnesium sulfate and then evaporation ofthe solvent was carried out. The residue was purified through silica gelcolumn chromatography (ether:n-hexane=1:1) to obtain[l-3-formyl-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](1.03 g, 82%).

IR (neat): 2950, 2870, 1680, 1620, 835 cm⁻¹.

NMR δ (CDCl₃): 9.78 (s, 1H), 6.71 (d, J=2 Hz, 2H), 4.60 (bs, 1H),3.00-4.20 (m, 6H), 0.90 (s, 9H).

Mass m/z (%): 295 (1), 159 (33) 85 (100), 75 (26), 73 (19), 67 (12), 57(14), 45 (14), 43 (22).

[α]_(D) ²⁰ =-77° (c=2.77, MeOH).

EXAMPLE 3

Oxalyl chloride (1.88 ml, 21.6 mmol) was dissolved in methylene chloride(55 ml) under argon gas atmosphere, and to the solution was added asolution of DMSO dissolved in methylene chloride (DMSO 3.39 ml, 47.7mmol/15 ml CH₂ Cl₂) at -60° C. for periods of 5 minutes. After themixture was stirred at -60° C. for 20 minutes, a solution ofd-1α-hydroxymethyl-2α-(3-hydroxypropyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxycyclopentane(1.48 g, 3.67 mmol) dissolved in methylene chloride (30 ml) was addeddropwise for periods of 5 minutes. The mixture was further stirred at-60° C. for 20 minutes, and then triethylamine (15.36 ml, 110.1 mmol)was added thereto and the temperature of the mixture was raised to roomtemperature. To the mixture was further added dibenzylammoniumtrifluoroacetate (1.14 g, 3.66 mmol) and methylene chloride wasdistilled out therefrom. To the residue was added benzene (45 ml) todissolve and the solution was stirred, under argon gas atmosphere, at50° to 70° C. for 16 hours. To the mixture was added water (50 ml) andextracted with ether. A separated ether layer was washed successivelywith a saturated aqueous ammonium chloride solution, a saturated aqueoussodium hydrogencarbonate solution and water, dried over anhydrousmagnesium sulfate and then distilled out the solvent therefrom. Theresidue was purified through silica gel column chromatography to obtainl-3-formyl-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxy-bicyclo[3.3.0]oct-2-ene(1.03 g, 74%).

EXAMPLE 4

In the method as described in Example 3, the same procedures werecarried out as in Example 3 except that[1α-hydroxymethyl-2α-(3-hydroxypropyl)-3β-(1-methyl-1-methoxyethyloxymethyl)-4α-tetrahydropyranyloxycyclopentane](1.13 g, 3.14 mmol) was employed as the starting material to obtain[3-formyl-6-exo-(1methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](690 mg, Yield: 65%) as colorless oily products.

IR (neat): 1680, 1620 cm⁻¹.

NMR δ (CDCl₃): 9.77 (s, 1H), 6.72 (d, J=2 Hz, 1H), 4.60 (bs, 1H),3.00-4.20 (m, 6H), 3.20 (s, 3H), 1.34 (s, 6H).

Mass m/z (%): 338, 306, 253.

EXAMPLE 5

In the method as described in Reference examples 1 to 5 and Examples 1and 2, the same procedures were carried out as in Reference examples 1to 2 and Examples 1 and 2 except that2-oxa-3-oxo-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane(1.11 g, 3.88 mmol) was employed as the starting material to obtain3-formyl-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(590 mg, Overall yield: 45%) as colorless oily products.

IR (neat): 1680, 1620 cm⁻¹.

NMR δ (CDCl₃): 9.77 (s, 1H), 6.72 (d, J=2 Hz, 1H), 4.60 (bs, 1H),3.00-4.20 (m, 6H), 3.20 (s, 3H), 1.34 (s, 6H).

Mass m/z (%): 338, 306, 253.

EXAMPLE 6

In the method as described in Reference examples 1 to 5 and Examples 1and 2, the same procedures were carried out as in Reference examples 1to 5 and Examples 1 and 2 except that2-oxa-3-oxo-6-exo-t-butyldimethylsilyloxymethyl-7-endo-(1-methyl-1-methoxyethyloxy)-bicyclo[3.3.0]octane(1.21 g, 3.88 mmol) was employed as the starting material to obtain3-formyl-6-exo-(t-butyldimethylsilyloxymethyl)-endo-(1-methyl-1-methoxyethyloxy)-bicyclo[3.3.0]oct-2-ene(522 mg, Overall yield: 42%) as colorless oily products.

IR (neat): 1680, 1620 cm⁻¹.

NMR δ (CDCl₃): 9.78 (s, 1H), 6.71 (d, J=2 Hz, 1H), 3.50-4.20 (m, 3H),3.20 (s, 3H), 3.00 (m, 1H), 1.34 (s, 6H), 0.90 (s, 9H).

Mass m/z (%): 368, 337, 311.

EXAMPLE 7

3-Carboxypropyltriphenylphosphonium bromide (5.58 g, 13 mmol) wassuspended in THF (60 ml) under argon gas atmosphere. To the solution wasadded a solution of potassium t-butoxide (3.01 g, 26 mmol) in THF (50ml) and the mixture was stirred at room temperature for 10 minutes. Tothe mixture was added dropwise a solution ofl-3-formyl-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(990 mg, 2.6 mmol) in THF (20 ml) and the miture was stirred at roomtemperature for 30 minutes. To the mixture was added a saturated aqueousammonium chloride solution and THF was distilled out under reducedpressure. The resultant aqueous layer was adjusted to pH 5 to 4 with a10% aqueous hydrochloric acid solution and extracted with ethyl acetate.The separated organic layer was dried over anhydrous magnesium sulfateand then solvents were distilled out. To the residue was added ether,insolubles were removed by filtration.

The residue obtained by evaporation of the solvent was purified throughsilica gel column chromatography to obtain3-(4-carboxy-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(1.05 g, Yield 90%). The ratio of (Z)-Isomer and (E)-Isomer was 2:1.

IR (neat): 3400, 1710, 840 cm⁻¹.

NMR δ (CDCl₃): 6.24 (d, J=16 Hz, 1/3H, trans), 5.95 (d, J=11 Hz, 2/3H,cis), 5.55 (bs, 1H), 5.30 (m, 1H), 4.60 (bs, 1H), 3.20-4.25 (m, 5H),2.95 (m, 1H), 0.90 (s, 9H).

Mass m/z (%): 450 (M⁺), 309, 265, 85.

EXAMPLE 8

3-(4-Carboxy-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(450 mg, 1 mmol) was dissolved in ether (5 ml) and to the mixtrue wasadded excess amount of diazomethane to obtain methyl ester thereof.Evaporation of the solvent in a draft chamber yieldedl-3-(4-methoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(464 mg, Yield: 100%) as scarcely colored oily products.

IR (neat: 2950, 2870, 1745, 840 cm⁻¹.

NMR δ (CDCl₃): 6.24 (d, J=16 Hz, 1/3H, trans), 5.98 (d, J=11 Hz, 2/3H,cis), 5.57 (bs, 1H), 5.30 (m, 1H), 4.60 (bs, 1H), 3.20-4.25 (m, 8H),2.95 (1H), 0.90 (s, 9H).

Mass m/z (%): 464 (trace, M⁺), 323 (20), 231 (28), 159 (29), 157 (16),117 (11), 85 (100), 75 (25), 73 (20), 67 (12), 57 (14), 43 (13), 41(13).

[α]_(D) ²⁰ =-50° (c=1.36, MeOH).

EXAMPLE 9

3-(4-Carboxy-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(450 mg, 1 mmol) was dissolved in acetnitrile (2 ml) and to the solutionwere added DBU (304 mg, 2 mmol) and ethyl iodide (468 mg, 3 mmol) atroom temperature and the mixture was further stirred for 3 hours. Afterthe reaction was stopped with the addition of a saturated aqueousammonium chloride solution, the mixture was extracted with ether. Theseparated ether layer was washed with a saturated saline solution anddried with anhydrous magnesium sulfate. After the mixture was distilledout the solvent, the residue was purified through silica gel columnchromatography to obtain3-(4-ethoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(400 mg, Yield: 84%) as colorless oile products.

IR (neat): 2950, 2870, 1745, 840 cm⁻¹.

NMR δ (CDCl₃): 6.24 (d, J=16 Hz, 1/3H, trans), 5.98 (d, J=11 Hz, 2/3H,cis), 5.57 (bs, 1H), 5.30 (m, 1H), 4.60 (bs, 1H), 4.20 (q, J=7 Hz, 2H),3.20-4.20 (m, 5H), 2.95 (m, 1H), 1.30 (t, J=7 Hz, 3H), 0.90 (s, 9H).

Mass m/z (%): 478 (M⁺), 433, 421, 393.

EXAMPLE 10

3-Carboxypropyltriphenylphosphonium bromide (5.58 g, 13 mmol) wassuspended in THF (60 ml) under argon gas atmosphere. To the solution wasadded a solution of potassium t-butoxide (3.01 g, 26 mmol) in THF (50ml) and the mixture was stirred at room temperature for 10 minutes. Tothe mixture was added dropwise a solution of[l-3-formyl-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](990 mg, 2.6 mmol) in THF (20 ml) and the miture was stirred at roomtemperature for 30 minutes. To the mixture was added a saturated aqueousammonium chloride solution and THF was distilled out under reducedpressure. The resultant aqueous layer was adjusted to pH 5 to 4 with a10% aqueous hydrochloric acid solution and extracted with ethyl acetate.The separated organic layer was dried over anhydrous magnesium sulfateand then solvents were distilled out. To the residue was added ether,insolubles were removed by filtration. To the filtrate was added inether solution of diazomethane. After disappearance of spot of[3-(4-carboxy-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2ene]was confirmed by using thin layer chromatography, to the mixture wasadded a small amount of formic acid and the mixture was immediatelywashed with a saturated aqueous sodium hydrogencarbonate solution and asaturated saline solution. The resultant mixture was dried overanhydrous magnesium sulfate and distilled out the solvents. The residuewas purified through silica gel column chromatography(ether:n-hexane=1:2) to obtain[l-3-(4-methoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](1.09 g, Yield: 90%). The ratio of (Z)-Isomer and (E)-Isomer was 2:1.

IR (neat): 2950, 2870, 1745, 840 cm⁻¹.

NMR δ (CDCl₃): 6.24 (d, J=16 Hz, 1/3H, trans), 5.98 (d, J=11 Hz, 2/3H,cis), 5.57 (bs, 1H), 5.30 (m, 1H), 4.60 (bs, 1H), 3.20-4.25 (m, 8H),2.95 (1H), 0.90 (s, 9H).

Mass m/z (%): 464 (trace, M⁺), 323 (20), 231 (28), 159 (29), 157 (16),117 (11), 85 (100), 75 (25), 73 (20), 67 (12), 57 (14), 43 (13), 41(13).

[α]_(D) ²⁰ =-50° (c=1.36, MeOH).

EXAMPLE 11

Under argon gas atmosphere, 3-carboxypropyltriphenylphosphonium bromide(5.58 g, 13 mmol) was dissolved in DMSO (10 ml). To the solution wasadded a solution of sodium salt of DMSO in DMSO (26 mmol, 13 ml) at roomtemperature and the mixture was stirred at the same condition for 10minutes. To the mixture was added dropwise a solution of-3-formyl-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(990 mg, 2.6 mmol) dissolved in DMSO (5 ml) and the mixture was stirredat room temperature for 30 minutes. A saturated aqueous ammoniumchloride solution was added thereto, and the separated aqueous layer wasadjusted to pH 4 to 5 with a 10% aqueous hydrochloric acid solution andthen extracted with ethyl acetate. The extract was washed with asaturated saline solution and dried with anhydrous magnesium sulfate.After evaporation of the solvent, the residue was treated withdiazomethane and purified through silica gel column chromatography(ether:n-hexane=1:2) to obtain l-3-(4-methoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(483 mg, Yield: 40%) as scarcely colored oily products. The ratio of(Z)-Isomer and (E)-Isomer was about 2:1 and the various spectrum datathereof were agreed with those of substance obtained in Example 8.

EXAMPLE 12

Under argon gas atmosphere, 3-carboxypropyltriphenylphosphosium brimide(5.58 g, 13 mmol) was suspended in a mixed solution of benzene (27 ml)and DMSO (0.4 ml). To the suspension was added a solution of t-amyloxysodium dissolved in benzene (26 mmol, 16.7 ml) at atmospherictemperature of 75° C., and the mixture was stirred at the sameconditions for 10 minutes. To the thus obtained mixture was added asolution ofl-3-formyl-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(990 mg, 2.6 mmol) dissolved in benzene (5 ml), and the mixture wasfurther stirred at 75° C. for 10 minutes. A saturated aqueous ammoniumchloride solution was added thereto, and the separated aqueous layer wasadjusted to pH 4 to 5 with a 10% aqueous hydrochloric acid solution andthen extracted with ethyl acetate. The extract was washed with asaturated saline solution and dried with anhydrous magnesium sulfate.After evaporation of the solvent, the residue was treated withdiazomethane and purified through silica gel column chromatography(ether:n-hexane=1:2) to obtainl-3-(4-methoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(613 mg, Yiled: 56%) as scarcely colored oily products. The ratio of(Z)-Isomer and (E)-Isomer was about 1:1 and the various spectrum datathereof were about the same with those of substance obtained in Example8.

EXAMPLE 13

Under argon gas atmosphere, 3-carboxypropyltriphenylphosphonium bromide(5.58 g, 13 mmol) was suspended in THF (60 ml). A THF (50 ml) solutionof potassium t-butoxide (3.01 g, 26 mmol) was added thereto and themixture was stirred at room temperature for 10 minutes. To the thusprepared mixture was added dropwise a THF (20 ml) solution of3-formyl-6-exo-(1-methyl-1methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(879 mg, 2.6 mmol), and the mixture was stirred at room temperature for30 minutes. To the mixture was added a saturated aqueous ammoniumchloride solution, and THF in the mixture was distilled off underreduced pressure. The resultant aqueous layer was adjusted to pH with a10% aqueous hydrochloric acid solution and extracted with ethyl acetate.The separated organic layer was dried with anhydrous magnesium sulfateand then the solvent was distilled off. To the residue was added etherand insolubles were removed by filtration. After evaporation of thesolvent, the residue was purified through silica gel columnchromatography to obtain3-(4-carboxy-1-butenyl)-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(965 mg, Yield: 91%). The ratio of (Z)-Isomer and (E)-Isomer was 2:1.

IR (neat): 3400, 1710, 840 cm⁻¹.

NMR δ (CDCl₃): 6.23 (d, J=16 Hz, 1/3H, trans), 5.95 (d, J=11 Hz, 2/3H,cis), 5.55 (bs, 1H), 5.30 (m, 1H), 4.60 (bs, 1H), 3.30-4.20 (m, 5H),3.20 (s, 3H), 2.95 (m, 1H), 1.34 (s, 6H).

Mass m/z (%): 408 (M⁺), 377, 364, 323.

Then,3-(4-carboxy-1-butenyl)-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-enewas subjected to treatment in ether with excess amount of diazomethaneto obtainl-3-(4-methoxycarbonyl-1-butenyl)-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-enequantitatively as colorless oily products.

IR (neat): 2950, 1742 cm⁻¹.

NMR δ (CDCl₃): 6.22 (d, J=16 Hz, 1/3H, trans), 5.95 (d, J=11 Hz, 2/3H,cis), 5.58 (bs, 1H), 5.30 (m, 1H), 4.62 (m, 1H), 3.67 (s, 3H), 3.25-4.10(m, 5H), 3.20 (s, 3H), 3.00 (m, 1H), 1.34 (s, 6H).

Mass m/z (%): 390, 350, 338, 332, 306, 248, 230, 204, 191, 143, 131,117, 91, 86, 85, 79, 73, 67.

[α]_(D) ²⁰ =-43.5° (c=0.718, MeOH).

EXAMPLE 14

Under argon gas atmosphere, 3-carboxypropyltriphenylphosphoniumbromide(5.58 g, 13 mmol) was suspended in THF (60 ml). To the suspension wasadded a solution of potassium t-butoxide (3.01 g, 26 mmol) in THF (50ml) and the mixture was stirred at room temperature for 10 minutes. Tothe mixture was added dropwise a solution of3-formyl-6-exo-t-butyldimethylsilyloxymethyl-7-endo-(1-methyl-1-methoxyethyloxy)-bicyclo[3.3.0]oct-2-ene(957 mg, 2.6 mmol) dissolved in THF (20 ml) and the mixture was stirredat room temperature for 30 minutes. A saturated aqueous ammoniumchloride solution was added thereto, and THF in the mixture wasdistilled out under reduced pressure. The resultant aqueous layer wasadjusted to pH 4 to 5 with a 10% aqueous hydrochloric acid solution andthen extracted with ethyl acetate. After the separated organic layer wasdried with anhydrous magnesium sulfate, the solvent was distilled out.To the residue was added ether and insolubles were removed byfiltration. Evaporation of the solvent, followed by purification throughsilica gel column chromatography (ether) to obtain3-(4-carboxy-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-(1-methyl-1-methoxyethyloxy)-bicyclo[3.3.0]oct-2-ene(1.00 g, Yield: 88%). The ratio of (Z)-Isomer and (E)-Isomer was 2:1.

IR (neat): 3400, 1710 cm⁻¹.

NMR δ (CDCl₃): 6.24 (d, J=16 Hz, 1/3H, trans), 5.95 (d, J=11 Hz, 2/3H,cis), 5.54 (bs, 1H), 5.30 (m, 1H), 3.30-4.20 (m, 3H), 3.20 (s, 3H), 2.95(m, 1H), 1.34 (s, 6H), 0.90 (s, 9H).

Mass m/z (%): 438 (M⁺), 407, 394, 381.

3-(4-Carboxy-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-(1-methyl-1-methoxyethyloxy)-bicyclo[3.3.0]oct-2-enewas treated with excess amount of diazomethane in ether solution toobtainl-3-(4-methyoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-(1-methyl-1-methoxyethyloxy)-bicyclo[3.3.0]oct-2-enequantitatively as colorless oily products.

IR (neat): 2960, 1745, 838 cm⁻¹.

NMR δ (CDCl₃): 6.24 (d, J=15 Hz, 1/3H, trans), 5.96 (d, J=11 Hz, 2/3H,cis), 5.60 (bs, 1H), 5.30 (m, 1H), 3.68 (s, 3H), 3.30-4.30 (m, 3H), 3.20(s, 3H), 3.00 (m, 1H), 1.33 (s, 6H), 0.90 (s, 9H), 0.05 (s, 6H).

Mass m/z (%): 420, 380, 363, 323, 231, 171, 157, 115, 89, 75, 73.

[α]_(D) ²⁰ =-21° (c=0.592, MeOH).

EXAMPLE 15

[l-3-(4-Methoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](547 mg, 1.18 mmol) was dissolved in methanol (10 ml). To the solutionwas added a 10% palladium/carbon (150 mg), the mixture was stirred atroom temperature for 1 hour and 10 minutes under hydrogen gasatmosphere. The catalyst was removed by filtration and solvents in thefiltrate were distilled out. The residue was purified through silica gelcolumn chromatography (ether:n-hexane=1:5) to obtain[l-3-(4-methoxycarbonylbutyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](509 mg, Yield: 93%).

IR (neat): 2950, 2880, 1745, 840 cm⁻¹.

NMR δ (CDCl₃): 5.25 (d, J=1 Hz, 1H), 4.60 (bs, 1H), 3.65 (s, 3H), 2.90(m, 1H), 0.90 (s, 9H).

Mass m/z (%): 325 (8), 233 (12), 159 (28), 85 (100), 75 (17), 73 (13).[α]_(D) ²⁰ =-12° (c=1.68, MeOH).

EXAMPLE 16

In methanol (10 ml) was dissolved[3-(4-methoxycarbonyl-1E-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-t-butyldimethylsilyloxy-bicyclo[3.3.0]oct-2-ene](583 mg, 1.18 mmol). To the solution was added a 10% palladium/carbon(150 mg) and the mixture was stirred under hydrogen atmosphere (1 atm.)at room temperature for 1 hour and 10 minutes. After the catalyst wasremoved by filtration, the solvent in the filtrate was distilled off.The residue was purified through silica gel column chromatography toobtain[l-3-(4-methoxycarbonylbutyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]oct-2-ene]380 mg, Yield: 65%).

IR (neat): 1745 cm⁻¹.

NMR δ (CDCl₃): 5.30 (1H), 3.85 (1H), 3.65 (s, 3H), 3.60 (2H), 2.90 (1H),0.90 (s, 9H), 0.85 (s, 9H), 0.05 (12H).

Mass m/z (%): 439 (M⁺ -57, 25), 243 (11), 233 (64), 207 (53), 201 (42),189 (11), 183 (21), 175 (19), 173 (14), 159 (14), 157 (14), 149 (17),148 (12), 147 (67), 73 (100).

Mili-MS: 439.2697 (M⁺ -t-Bu); M⁺ -t-Bu=C₂₃ H₄₃ O₄ Si₂ =439.2697.

EXAMPLE 17

In the method as described in Example 15, the same procedures werecarried out as in Example 15 except that[l-3-(4-methoxycarbonyl-1-butenyl)-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](498 mg, 1.18 mmol) was employed as the starting material to obtain[3-(4-methoxycarbonylbutyl)-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](425 mg, Yield: 85%).

IR (neat): 2950, 2880, 1742, 840 cm⁻¹.

NMR δ (CDCl₃): 5.23 (d, J=1 Hz, 1H), 4.60 (bs, 1H), 3.65 (s, 3H),3.40-4.10 (m, 5H), 3.20 (s, 3H), 2.90 (m, 1H), 1.34 (s, 6H).

Mass m/z (%): 424 (M⁺), 393, 392, 339.

EXAMPLE 18

[l-3-(4-Methoxycarbonylbutyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](585 mg, 1.26 mmol) was dissolved in THF (5 ml). To the solution wasadded tetra-n-butylammonium fluoride (1M THF solution 2.5 ml, 2.5 mmol),the mixture was stirred at room temperature for 3 hours. To the mixturewas added a saturated saline solution and THF was distilled outtherefrom under reduced pressure. After the resultant aquesous layer wasextracted with ether, the separated ether layer was dried over anhydrousmagnesium sulfate and then solvents were distilled out. The residue waspurified through silica gel column chromatography to obtain[l-3-(4-methoxycarbonylbutyl)-6-exo-hydroxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](425 mg, Yield: 95.2%).

IR (neat): 3480, 2950, 2880, 1740 cm⁻¹.

NMR δ (CDCl₃): 5.25 (d, J=1 Hz, 1H), 4.60 (m, 1H), 3.66 (s, 3H), 3.00(m, 1H).

Mass m/z (%): 352 (trace, M⁺), 268 (3), 85 (100), 67 (11), 57 (10), 41(11).

[α]_(D) ²⁰ =-19° (c=2.09, MeOH).

EXAMPLE 19

[l-3-(4-methoxycarbonylbutyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]oct-2-ene](4.8 mg, 0.01 mmol) was dissolved in hydrated ethanol (ethanol:H₂O=75:1) (0.15 ml), and pyridinium p-toluenesulfonate (1 mg, 0.004 mmol)was added thereto and the mixture was stirred at 25° C. for 16 hours.After the mixture was diluted with ether, the resultant mixture waswashed successively with a 1% aqueous HCl solution, a saturated aqueousNaHCO₃ solution and a saturated saline solution, and dried withanhydrous magnesium sulfate. After evaporation of the solvent, theresidue was purified through silica gel column chromatography. As aresult, 2.3 mg (Yield: 60%) of[3-(4-methoxycarbonylbutyl)-6-exo-hydroxymethyl-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]oct-2-ene]was obtained as substantially colorless oily products.

IR (neat): 3480, 1740 cm⁻¹.

NMR δ (ppm): 5.30 (1H), 3.85 (1H), 3.65 (s, 3H), 3.60 (2H), 2.90 (1H).

EXAMPLE 20

[3-(4-Methoxycarbonylbutyl)-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](424 mg, 1 mmol) was dissolved in THF (11ml) and the solution was addedunder ice-cooling a 0.5N HCl (5.5 ml) and stirred at the sametemperature for 10 minutes. Ethyl acetate (109 ml) was added thereto andthe separated organic layer was washed with water and then a saturatedsaline solution and dried with anhydrous magnesium sulfate. Evaporationof the solvent, followed by purification through silica gel columnchromatography to obtain[l-3-(4-methoxycarbonylbutyl)-6-exo-hydroxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](334 mg, Yield: 95%) as colorless oily product.

Various spectrum data of the thus obtained compound was absolutelyagreed with those of the substance obtained in Example 18.

EXAMPLE 21

Collins reagent (CrO₃.2Py, 660 mg, 2.56 mmol) and Celite (660 mg) weresuspended in methylene chloride under argon gas atmosphere. A solutionof[l-3-(4-methoxycarbonylbutyl)-6-exo-hydroxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octo-2-ene](50 mg, 0.142 mmol) dissolved in methylene chloride (2.5 ml) was addedto the suspension and stirred at 0° C. for 30 minutes. To the mixturewas added 1.32 g of sodium hydrogensulfate monohydrate and the mixturewas further stirred at 0° C. for 10 minutes. The reaction mixture wasfiltrated by using anhydrous magnesium sulfate as a filter aid and thefilter aid was washed with methylene chloride. The filtrates werecombined and evaporated the solvent to obtain[3-(4-methoxycarbonylbutyl)-6-exo-formyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](48 mg, Yield: 96%).

On the other hand, sodium hydride (60% of oily mixture, 11 mg, 0.28mmol) was washed with pentane under argon gas atmosphere and suspendedin 3 ml of DME (dimethoxyethane). To the suspension was added a solutionof dimethyl(2-oxoheptyl)phosphonate (64 mg, 0.29 mmol) dissolved in DME(3 ml) and the mixture was stirred at room temperature for 25 minutes.To the mixture was added a solution of[3-(4-methoxycarbonylbutyl)-6-exo-formyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](48 mg) dissolved in DME (3 ml), the mixture was stirred at roomtemperature for an hour and then a saturated aqueous ammonium chloridesolution was added thereto. Evaporation of DME under reduced pressurefollowed by extraction with ethyl ether. The separated ether layer waswashed with a saturated saline solution. After the mixture was driedover anhydrous magnesium sulfate, the residue obtained by evaporation ofthe solvent was purified through silica gel column chromatography(ether:n-hexane=2:5) to obtain[3-(4-methoxycarbonylbutyl)-6-exo-(3-oxo-trans-1-octenyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](35 mg, Yield: 57%).

IR (neat): 2950, 2880, 1742, 1698, 1672, 1628 cm⁻¹.

NMR δ (CDCl₃): 6.80 (m, 1H), 6.17 (dxd, J=16 Hz, J=4 Hz, 1H), 5.30 (d,J=1 Hz, 1H), 4.65 and 4.55 (each bs, total 1H), 3.68 (s, 3H), 3.00 (m,1H).

Mass m/z (%): 362 (10), 318 (13 ), 85 (100), 67 (16), 57 (18), 55 (13),43 (20), 41 (20).

EXAMPLES 22 TO 25

Various kinds of the (3-oxo-1-alkenyl)-cis-bicyclo[3.3.0]octenederivatives as shown in Table 1 were synthesized by the reaction witheach of dimethyl-(2-oxoalkyl)phosphonate in the same manner as inExample 21. The results of the synthesis are shown in Table 1 and thespectrum data thereof are shown in Table 2 below.

                                      TABLE 1                                     __________________________________________________________________________    Example No.                                                                          Starting phosphonate Reaction product                                                                              Yield (%)                         __________________________________________________________________________    22                                                                                    ##STR19##                                                                                          ##STR20##      65                                23                                                                                    ##STR21##                                                                                          ##STR22##      52                                24                                                                                    ##STR23##                                                                                          ##STR24##      76                                25                                                                                    ##STR25##                                                                                          ##STR26##      45                                __________________________________________________________________________

                  TABLE 2                                                         ______________________________________                                                  Characteristic  NMR spectrum                                                  IR spectrum (cm.sup.-1)                                                                       δ ppm                                         Example   ν.sub.C═O                                                                              olefin proton                                       No.       ester    keton      ring  side chain                                ______________________________________                                        22        1742     1698, 1672,                                                                              5.28  6.80, 6.20                                                   1628                                                       23        1742     1698, 1672,                                                                              5.28  6.80, 6.20                                                   1628                                                       24        1742     1698, 1672,                                                                              5.28  6.75, 6.20                                                   1628             5.10                                      25        1742     1692, 1622 5.28  6.80, 6.55                                ______________________________________                                    

EXAMPLE 26

[3-(4-Methoxycarbonylbutyl)-6-exo-hydroxymethyl-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]oct-2-ene](118 mg, 0.31 mmol) was dissolved in a mixed solvent of DMSO (3.5 ml)and triethylamine (0.26 ml), and a DMSO solution (2.5 ml) of SO₃.py (148mg, 0.93 mmol) was added thereto at room temperature while stirring.After the mixture was stirred at the same condition for 1 hour and 20minutes, it was poured into ice-cold water and then extracted withether. The separated ether layer was washed with water and a saturatedsaline solution, and dried with anhydrous magnesium sulfate. About 110mg of an aldehyde derivative was obtained after evaporation of thesolvent and it was employed to the next reaction without purification.

Sodium hydride (60% oily substance, 17 mg, 0.43 mmol) was washed withpentane under argon gas atmosphere, and suspended in 3 ml of THF. To thesuspension was added a 10.5 ml of THF solution ofdimethyl(2-oxoheptyl)phosphonate (103 mg, 0.47 mmol) and the mixture wasstirred at room temperature for 30 minutes.

To the thus prepared anion solution was added the previously preparedTHF solution (1.5 ml) of the aldehyde derivative and the mixture wasstirred at the same conditions for 40 minutes, then the reaction wasstopped by adding 0.11 ml of acetic acid. After the resultant mixturewas diluted with ether, the mixture was washed with a saturated aqueousNaHCO₃ solution and dried with anhydrous magnesium sulfate. Evaporationof the solvent, followed by purification through silica gel columnchromatography to obtain[3-(4-methoxycarbonylbutyl)-6-exo-(3-oxo-trans-1-octenyl)-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]oct-2-ene](107 mg, Yield: 73%) as substantially colorless oily products.

IR (neat): 1742, 1698, 1672, 1628 cm⁻¹.

NMR δ (ppm): 6.80 (dd, 1H), 6.17 (dd, 1H), 5.30 (d, J=1 Hz, 1H), 4.00(m, 1H), 3.68 (s, 3H), 3.00 (m, 1H).

EXAMPLE 27

[3-(4-Methoxycarbonylbutyl)-6-exo-(3-oxo-trans-1-octenyl)-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]oct-2-ene](93 mg, 0.20 mmol) was dissolved in a 65% hydrated acetic acid (1.7 ml)and tetrahydrofuran (0.17 ml) and the solution was stirred at 50° C. foran hour. The resultant mixture was poured into a saturated aqueousNaHCO₃ solution and extracted with ethyl acetate. The separated organiclayer was washed with water and a saturated saline solution, and driedwith anhydrous magnesium sulfate. Evaporation of the solvent, followedby purification through silica gel column chromatography to obtain 72 mg(Yield: 99%) of[3-(4-methoxycarbonylbutyl)-6-exo-(3-oxo-trans-1-octenyl)-7-endo-hydroxybicyclo[3.3.0]oct-2-ene]as substantially colorless oily products.

IR (neat): 3470, 2950, 1740, 1699, 1675, 1625 cm⁻¹.

NMR δ (ppm): 6.55 (dd, J=16 Hz, 8 Hz, 1H), 6.16 (d, J=16 Hz, 1H), 5.30(broad s, 1H), 3.90 (qd, J=8 Hz, 2 Hz, 1H), 3.68 (s, 3H), 3.00 (m, 1H),1.80-2.80 (m, 12H), 1.10-2.80 (m, 10H), 0.90 (t, J=6 Hz, 3H).

[α]_(D) ²⁰ =+105° (c=1.488, MeOH).

REFERENCE EXAMPLE 7

[3-(4-Methoxycarbonylbutyl)-6-exo-(3-oxo-trans-1-octenyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](32 mg, 0.072 mmol) was dissolved in methanol (5 ml). The solution wascooled to -20° C. and excess amount of sodium borohydride was addedthereto. After the mixture was stirred at -20° C. for 20 minutes, excessamount of acetone was added thereto. After the temperature of themixture was returned to room temperature, to the mixture was added asaturated aqueous ammonium chloride solution and methanol and acetonewere distilled by evaporation under reduced pressure. The resultantaqueous layer was extracted with ether and then dried with anhydrousmagnesium chloride to obtain[3-(4-methoxycarbonylbutyl)-6-exo-(3-hydroxy-trans-1-octenyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](32 mg, Yield: 100%).

IR (neat): 3470, 3230, 2950, 2880, 1742 cm⁻¹.

NMR δ (CDCl₃): 5.57 (m, 2H), 5.28 (d, J=1 Hz, 1H), 4.63 (bs, 1H), 3.65(s, 3H), 2.95 (m, 1H).

Mass m/z (%): 430 (1, M⁺ -H₂ O), 302 (15), 85 (100), 67 (13), 57 (16),55 (11), 43 (17), 41 (18).

REFERENCE EXAMPLES 8 TO 11

Various kinds of 3-oxo-1-alkenyl-cis-bicyclo[3.3.0]octene derivativeswere reduced in the same manner as in Reference example 7. The obtainedresults and spectrum data thereof were shown in Table 3 below.

                                      TABLE 3                                     __________________________________________________________________________                                 Characteristic                                                                       NMR spectrum                                                           IR spectrum                                                                          (δ ppm)                             Reference                    (cm.sup.-1)                                                                          olefin proton                             example No.                                                                          R               Yield (%)                                                                           .sup.ν OH                                                                     .sup.ν CO                                                                      ring                                                                             side chain                             __________________________________________________________________________     8                                                                                    ##STR27##      100   3500                                                                             1742                                                                              5.30                                                                             5.60                                    9                                                                                    ##STR28##      100   3480                                                                             1740                                                                              5.28                                                                             5.62                                   10                                                                                    ##STR29##      100   3480, 3230                                                                       1742                                                                              5.30                                                                             5.60, 5.13                             11                                                                                    ##STR30##      100   3500, 3220                                                                       1742                                                                              5.30                                                                             5.62                                   __________________________________________________________________________

REFERENCE EXAMPLE 12

[3-(4-Methoxycarbonylbutyl)-6-exo-(3-oxo-trans-1-octenyl)-7-endo-hydroxybicyclo[3.3.0]oct-2-ene](36 mg, 0.1 mmol) was dissolved in anhydrous toluene (1 ml).

Prior to the above procedure, diisobutylaluminum hydride in toluenesolution (331 mg, 1.5 mmol) was added to 2,6-di-t-butyl-4-methylphenol(331 mg, 1.5 mmol) in toluene (2.6 ml) solution under ice-cooling, andthe solution was stirred at the same condition for an hour. To the thusprepared solution was added the previously prepared toluene solutioncontaining a starting mateial at -78° C. Temperature of the mixture waselevated to -10° C. over 2.5 hours and the mixture was stirred at thesame temperature for 3 hours. The reaction was stopped by adding 0.34 mlof water and stirring was further continuted at room temperature for anhour. After insolubles were removed by precipitation, solvents weredistilled out by evaporation. The residue was purified through silicagel column chromatography to obtain[3-(4-methoxycarbonylbutyl)-6-exo-(3α-hydroxy-trans-1-octenyl)-7-endo-hydroxybicyclo[3.3.0]oct-2-ene](20.6 mg, Yield: 57%) and[3-(4-methoxycarbonylbutyl)-6-exo-(3β-hydroxy-trans-1-octenyl)-7-endo-hydroxybicyclo[3.3.0]oct-2-ene](8.3 mg, Yield: 23%) as oily products, respectively. The spectrum dataof α-epimer are shown in the following. The spectrum data of β-epimerare the same to those of α-epimer.

IR (neat): 3400, 2970, 2930, 2870, 1742 cm⁻¹.

NMR δ (ppm): 5.60 (m, 2H), 5.33 (bs, 1H), 4.12 (m, 1H), 3.80 (m, 1H),3.69 (s, 3H), 3.00 (m, 1H).

Mass m/z (%): 346 (25, M⁺ -H₂ O), 328 (18), 315 (9), 302 (71), 275 (15),247 (11), 232 (32), 199 (17), 193 (19), 180 (30), 179 (27).

REFERENCE EXAMPLE 13

[3-(4-Methoxycarbonylbutyl)-6-exo-(3-hydroxy-trans-1-octenyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene](32 mg, 0.072 mmol) was dissolved in a mixed solution of aceticacid:water:THF (0.5 ml) (3:1:1, volume ratio) and the solution wasstirred at 45° to 50° C. for 5 hours. After dilution with ether, themixture was neutralized with a saturated aqueous sodiumhydrogen-carbonate solution. After the separated ether layer was washedwith a saturated saline solution, dired with anhydrous magnesiumsulfate. Evaporation of the solvent followed by purification throughsilica gel column chromatography (ether:n-hexane=5:1 toether:methanol=40:1) to obtain[3-(4-methoxycarbonylbutyl)-6-exo-(3α-hydroxy-trans-1-octenyl)-7-endo-hydroxybicyclo[3.3.0]oct-2-ene](13 mg, Yield: 48%) as a higher polarity fraction and[3-(4-methoxycarbonylbutyl)-6-exo-(3β-hydroxy-trans-1-octenyl)-7-endo-hydroxybicyclo[3.3.0]-oct-2-ene](7 mg, Yield: 26%) as a lower polarity fraction. The spectrum data of anα-epimer are shown in the following. The spectrum data of a β-epimer arethe same as those of the α-epimer.

IR (neat): 3400, 2970, 2930, 2870, 1742 cm⁻¹.

NMR δ (CDCl₃): 5.60 (m, 2H), 5.33 (bs, 1H), 4.12 (m, 1H), 3.69 (s, 3H),3.00 (m, 1H).

Mass m/z (%): 346 (25, M⁺ -H₂ O), 328 (18), 315 (9), 302 (71), 275 (15),247 (11), 232 (32), 199 (17), 193 (19), 180 (30), 179 (27).

REFERENCE EXAMPLES 14 TO 17

By using various kinds of[3-(4-methoxycarbonylbutyl)-6-exo-(3-hydroxy-trans-1-alkenyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene],elimination reaction of each THF group was carried out in the samemanner as in Reference example 13 and then each isomer based on the15-position hydroxy group in the resultant mixture was separated byusing silica gel column chromatography. The obtained results andspectrum data thereof are shown in Table 4 below. In each cases, anisomer having higher polarity named α-epimer and an isomer having lowerpolarity of β-epimer.

                                      TABLE 4                                     __________________________________________________________________________                                              NMR spectrum                        Reference                       Characteristic                                                                          (δ ppm)                       example               Yield (%) IR spectrum (cm.sup.-1)                                                                 olefin proton                       No.   R               α-epimer                                                                     β-epimer                                                                      ν.sub.OH                                                                        ν.sub.C═O                                                                   ring                                                                             side chain                       __________________________________________________________________________    14                                                                                   ##STR31##      46   31   3400 1740 5.33                                                                             5.61                             15                                                                                   ##STR32##      39   20   3400 1740 5.32                                                                             5.61                             16                                                                                   ##STR33##      41   16   3400 1741 5.33                                                                             5.62                             17                                                                                   ##STR34##      45   22   3420 1742 5.34                                                                             5.65                             __________________________________________________________________________     *All the spectrum data shown are of α-epimer. The spectrum data of      β-epimer are the same.                                              

REFERENCE EXAMPLE 18

[3-(4-Methoxycarbonylbutyl)-6-exo-(3α-hydroxy-trans-1-octenyl)-7-endo-hydroxybicyclo[3.3.0]-oct-2-ene](10 mg, 0.027 mmol) was dissolved in methanol (0.3 ml). To the solutionwas added a 10% aqueous sodium hydroxide solution (0.2 ml) at 0° C.After stirring for 9 hours at 0° C., the mixture was neutralized with a10% hydrochloric acid solution while cooling. Evaporation of methanolunder reduced pressure, followed by adjustment to pH 3 to 4 and then themixture was extracted with ethyl acetate. The extract was dried withanhydrous magnesium sulfate and distilled the solvent to obtain[9(0)-methano-Δ⁶(9α) -PGI₁ ] (10 mg, Yield: 100%).

IR (neat): 3350, 2910, 2850, 1700, 1450, 1250 cm⁻¹.

NMR δ(CDCl₃): 5.60 (m, 2H), 5.33 (bs, 1H), 4.11 (m, 1H), 3.80 (m, 1H),3.00 (m, 1H), 0.90 (t, J=6 Hz, 3H).

Mass (CI, NH₃) m/z (%): 368 (25, M⁺ +NH₄).

Melting point: 73° to 79° C.

[α]_(D) ²⁵ =+16° (c=0.25, MeOH).

15β-Epimer was hydrolyzed in the same manner as mentioned above toobtain 15β isomer of 9(0)-methano-Δ⁶(9α) -PGI₁. The spectrum data (IR,NMR, Mass) thereof agreed with that of 9(0)-methano-Δ⁶(9α) -PGI₁.

REFERENCE EXAMPLES 19 TO 22

In the same manner as in Reference example 18, various kinds of[3-(4-methoxycarbonylbutyl)-6-exo-(3α-hydroxy-trans-1-alkenyl)-7-endo-hydroxybicyclo[3.3.0]oct-2-ene]were hydrolyzed to obtain various kinds of [9(0)-methano-Δ⁶(9α) -PGI₁derivatives]. The obtained results and spectrum data thereof are shownin Table 5 below.

In the same manner as above, 15β-epimer was also hydrolyzed to obtain15β-isomer of 9(0)-methano-Δ⁶(9α) -PGI₁ derivatives. The spectrum data(IR, NMR, Mass) thereof agreed with that of 9(0)-methano-Δ⁶(9α) -PGI₁derivatives.

                                      TABLE 5                                     __________________________________________________________________________                                        NMR spectrum                              Reference                 Characteristic                                                                          (δ ppm)                             example               Yield                                                                             IR spectrum (cm.sup.-1)                                                                 olefin proton                             No.   R               (%) ν.sub.OH                                                                        ν.sub.C═O                                                                   ring                                                                             side chain                             __________________________________________________________________________    19                                                                                   ##STR35##      97  3400 1710 5.58                                                                             5.33                                   20                                                                                   ##STR36##      73  3400 1710 5.60                                                                             5.32                                   21                                                                                   ##STR37##      95  3400 1710 5.60                                                                             5.33                                   22                                                                                   ##STR38##      100 3400 1710 5.62                                                                             5.32                                   __________________________________________________________________________

REFERENCE EXAMPLE 23

l-3-(4-Methoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]-oct-2-ene(mixture of cis: trans=2:1, 116 mg, 0.25 mmol) andmethylbenzoatetricarbonylchromium (14 mg. 0.05 mmol) were dissolved inacetone (10 ml) and a cycle of cooling-diminished pressure-dissolutionwere repeated to degas. The resultant mixture was transffered into 100ml of autoclave and 70 kg/cm² of hydrogen gas was charged therein. Afterthe reaction at 120° C. for 15 hours, evaporation of the solventfollowed by purification through silica gel column chromatography(ether: n-hexane=1:5) to obtain3E-(4-methoxycarbonylbutylidene)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane(111 mg, Yield: 95%). The obtained material did not contain at all aZ-Isomer due to a double bond from the result of analysis by using gaschromatography.

IR (neat): 2970, 2880, 1747, 840 cm⁻¹.

NMR δ (CDCl₃): 5.23 (t, J=7 Hz, 1H), 4.66 (m, 1H), 3.70 (s, 3H),3.30-4.10 (m, 5H), 0.90 (s, 9H), 0.05 (s, 6H).

Mass m/z (%): 466 (M⁺, trace), 325 (37), 233 (70), 201 (44), 159 (100),85 (100), 75 (75), 73 (65), 67 (43), 57 (40).

REFERENCE EXAMPLE 24

l-3-(4-Methoxycarbonyl-1-butenyl)-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(106 mg, 0.25 mmol) and methylbenzoatetricarbonylchromium (14 mg, 0.05mmole) were dissolved in acetone (10 ml) and then degassed. In 100 ml ofautoclave and under 70 kg/cm² of hydrogen gas pressure, the reaction wascarried out at 120° C. for 15 hours. Evaporation of the solvent followedby purification through silica gel column chromatography (ether:n-hexane=1:4) to obtain3E-(4-methoxycarbonylbutylidene)-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane(95 mg, Yield: 90%). The obtained material did not contain at all aZ-Isomer due to a double bond from the result of analysis by using gaschromatography.

IR (neat): 2970, 2880, 1743, 835 cm⁻¹.

NMR δ (CDCl₃): 5.20 (t, J=7 Hz, 1H), 4.65 (m, 1H), 3.70 (s, 3H),3.30-4.10 (m, 5H), 3.20 (s, 3H), 1.33 (s, 6H).

Mass m/z (%): 424 (M⁺), 393, 340, 85.

REFERENCE EXAMPLE 25

l-3-(4-Methoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-(1-methyl-1-methoxyethyloxy)bicyclo[3.3.0]oct-2-ene(113 mg, 0.25 mmol) and methylbenzoatetricarbonylchromium (14 mg, 0.05mmol) were dissolved in acetone (10 ml) and then degassed. In 100 ml ofautoclave and under 70 kg/cm² of hydrogen gas pressure, the reaction wascarried out at 120° C. for 15 hours. Evaporation of the solvent followedby purification through silica gel column chromatography (ether:n-hexane=1:4) to obtain3E-(4-methoxycarbonylbutylidene)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-(1-methyl-1-methoxyethyloxy)-bicyclo[3.3.0]octane(102 mg, Yield: 90%). The presence of a Z-Isomer structure could not beadmitted as the result of analysis by using gas chromatography.

IR (neat): 2970, 2880, 1743, 835 cm⁻¹.

NMR δ (CDCl₃): 5.21 (t, J=7 Hz, 1H), 3.70 (s, 3H), 3.30-4.10 (m, 3H),3.20 (s, 3H), 1.33 (s, 6H), 0.90 (s, 9H), 0.05 (s, 6H).

Mass m/z (%): 454, 422, 382, 73, 59, 41.

REFERENCE EXAMPLE 26

l-3-(4-Carboxy-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(113 mg, 0.25 mmol) and methylbenzoatetricarbonylchromium (14 mg, 0.05mmol) were dissolved in acetone (10 ml) and then degassed. In 100 ml ofautoclave and under 70 kg/cm² of hydrogen gas pressure, the reaction wascarried out at 120° C. for 15 hours. Evaporation of the solvent followedby purification through silica gel column chromatography (ether) toobtain3E-(4-carboxybutylidene)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane(62 mg, Yield: 55%). The obtained material was treated with diazomethaneto obtain methyl ester derivative. The spectrum data thereof arecompletely agreed with that of the compound obtained in Referenceexample 10. From the analysis of the methyl ester derivative by using agas chromatography, the presence of Z-Isomer could not be admitted.

REFERENCE EXAMPLE 27

3E-(4-methoxycarbonylbutylidene)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane(100 mg, 0.21 mmol) was dissolved in THF (1.5 ml). To the solution wasadded tetra-n-butylammonium fluoride (1M THF solution 0.32 ml, 0.32mmol) and the mixture was stirred at room temperature for 13 hours.Then, a saturated saline solution was added thereto and THF wasdistilled from the mixture under reduced pressure. The resultant aqueouslayer was extracted with ether, dried with anhydrous magnesium sulfateand distilled out the solvent therefrom. The residue was purifiedthrough silica gel column chromatography (ether: n-hexane=3:2) to obtaind-3E-(4-methoxycarbonylbutylidene)-6-exo-hydroxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane(74 mg, 98%).

IR (neat): 3480, 2950, 1741 cm⁻¹.

NMR δ (CDCl₃): 5.22 (t, J=7 Hz, 1H), 4.65, (m, 1H), 3.65 (s, 3H),3.30-4.00 (m, 5H).

Mass m/z (%): 334 (2), 268 (19), 250 (15), 232 (38), 219 (22), 91 (26),86 (33), 85 (100).

[α]_(D) ²⁰ =+6° (c=1.476, MeOH).

REFERENCE EXAMPLE 28

3E-(4-methoxycarbonylbutylidene)-6-exo-(1-methyl-1-methoxyethyloxymethyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane(95 mg, 0.22 mmol) was dissolved in THF (2.4 ml) and under ice-cooling,a 0.5N HCl (1.2 ml) was added to the solution and the mixture wasstirred at the same condition for 10 hours. Ethyl acetate (24 ml) wasadded thereto and a separated organic layer was washed with water and asaturated saline solution and then dried with anhydrous magnesiumsulfate. Evaporation of the solvent followed by purification throughsilica gel column chromatography (ether: n-hexane=1:2) to obtaind-3E-(4-methoxycarbonylbutylidene)-6-exo-hydroxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane(74 mg, Yield: 90%).

Various spectrum data thereof was completely agreed with that of thecompound obtained in Reference example 27.

REFERENCE EXAMPLE 29

3E-(4-methoxycarbonylbutylidene)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-(1-methyl-1-methoxyethyloxy)bicyclo[3.3.0]octane(50 mg, 0.11 mmol) was dissolved in THF (1 ml) and to the solution wasadded a THF solution of tetra-n-butylammonium fluoride (0.2 ml) andstirred at room temperature for 13 hours. After evaporation of thesolvent under reduced pressure, to the residue was added water andextracted with ether. The separated wther layer was washed with asaturated saline solution and dried with anhydrous magnesium sulfate.After evaporation of the solvent, the residue was purified throughsilica gel column chromatography (ether: n-hexane=1:1) to obtain3E-(4-methoxycarbonylbutylidene)-6-exo-hydroxymethyl-7-endo-(1-methyl-1-methoxyethyloxy)bicyclo[3.3.0]octane(35 mg, Yield: 95%) as colorless oily products.

IR (neat): 3480, 2950, 1740 cm⁻¹.

NMR δ (CDCl₃): 5.22 (t, J=7 Hz, 1H), 3.65 (s, 3H), 3.30-4.20 (m, 3H),3.20 (s, 3H), 1.30 (s, 6H).

Mass m/z (%): 340, 322, 209, 268, 73.

REFERENCE EXAMPLE 30

Under argon gas atmosphere,d-3E-(4-methoxycarbonylbutylidene)-6-exo-hydroxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane(49 mg, 0.14 mmol) and triethylamine (0.12 ml) were dissolved in DMSO(1.5 ml). To the mixture was added a sulfur trioxide.pyridine complex(67 mg, 0.42 mmol) dissolved in DMSO (1 ml) and the mixture was stirredat room temperature for an hour. The thus obtained mixture was pouredinto ice-cold water and extracted with ether. The separated ether layerwas washed with water and a saturated saline solution. After drynesswith anhydrous magnesium sulfate, evaporation of the solvent to obtain3E-(4-methoxycarbonylbutylidene)-6-exo-formyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane.

On the other hand, sodium hydride (60% oily material, 8 mg, 0.2 mmol)was washed with pentane under argon gas atmosphere and then suspended inTHF (1.4 ml). To the suspension was added a solution ofdimethyl(2-oxoheptyl)phosphonate (47 mg, 0.21 mmol) in THF (0.2 ml) andthe mixture was stirred at room temperature for 30 minutes. To the thusprepared mixture was added the previously prepared THF solution (0.6 ml)of3E-(4-methoxycarbonylbutylidene)-6-exo-formyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octaneand the mixture was stirred at room temperature for 30 hours. Asaturated aqueous ammonium chloride solution was added thereto and themixture was extracted with ether. The separated ether layer was washedwith a saturated saline solution and dried with anhydrous magnesiumsulfate. Evaporation of the solvent followed by purification throughsilica gel column chromatography (ether: n-hexane=2:5) to obtain3E-(4-methoxycarbonylbutylidene)-6-exo-(3-oxo-trans-1-octenyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane(52 mg, Yiled: 84%).

IR (neat): 2950, 1740, 1700, 1675, 1630 cm⁻¹.

NMR δ (CDCl₃): 6.75 (m, 1H), 6.17 & 6.13 (2×d, J=16 Hz, 1H), 5.25 (t,J=7 Hz, 1H), 4.60, (m, 1H), 3.68 (s, 3H), 3.30-4.20 (m, 3H), 0.90 (t,J=6 Hz, 1H).

Mass m/z (%): 362 (5), 344 (7), 167 (13), 149 (41), 85 (34), 74 (23), 73(25), 61 (34), 59 (31), 57 (31), 45 (100), 43 (77), 31 (78), 29 (51).

REFERENCE EXAMLE 31

3E-(4-methoxycarbonylbutylidene)-6-exo-(3-oxo-trans-1-octenyl)-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane(50 mg, 0.11 mmol) was dissolved in THF (0.09 ml) and a 65% aqueousacetic acid solution (0.9 ml) was added thereto at room temperature.After the mixture was stirred at 50° C. for 2 hours, the mixture waspoured into a cooled saturated aqueous sodium hydrogencarbonatesolution. The resultant mixture was extracted with ether, washed with asaturated saline solution and dried with anhydrous magnesium sulfate.Evaporation of the solvent followed by purification through silica gelcolumn chromatography (ether: n-hexane=3:2) to obtaind-3E-(4-methoxycarbonylbutylidene)-6-exo-(3-oxo-trans-1-octenyl)-7-endo-hydroxybicyclo[3.3.0]octane(39 mg, Yield: 96%).

The data of the resultant substance were completely agreed with the datadescribed in the literature (Tetrahedron, Vol. 37, No. 25, pp.4391-4399, 1981).

IR (neat): 3430, 1740, 1695, 1670, 1625, 1435, 1375, 1320, 1250, 1170,1135, 1080, 986 cm⁻¹.

NMR δ (CDCl₃): 6.77 (dd, J=15.5 Hz, 8.0 Hz, 1H), 6.17 (d, J=15.5 Hz,1H), 5.25 (m, 1H), 3.90 (m, 1H), 3.66 (s, 3H), 0.90 (m, 3H).

Mass m/z (%): 362, 344, 318, 313, 245, 179, 164, 147, 131, 129, 105.

Further, it is confirmed that the thus obtained compound is sole one dueto TLC analysis by using a mixed solvent of ethyl acetate:cyclohexane=1:2 which is an eluent capable of separating the E-Isomerand Z-Isomer depending on the above literature. In the literature(Tetrahedron, Vol. 37, No. 25, pp. 4391-4399, 1981), the above compoundhas been led to carbacycline at high yield.

REFERENCE EXAMPLE 32

In the method as described in Reference example 30, the same procedureswere carried out as in Reference example 30 except that3E-(4-methoxycarbonylbutylidene)-6-exo-hydroxymethyl-7-endo-(1-methyl-1-methoxyethyloxy)-bicyclo[3.3.0]octane(35 mg, 0.10 mmol) was employed as the starting material to obtain3E-(4-methoxycarbonylbutylidene)-6-exo-(3-oxo-1-trans-octenyl)-7-endo-(1-methyl-1-methoxyethyloxy)bicyclo[3.3.0]octane(35 mg, Yield: 80%) as substantially colorless oily products.

IR (neat): 2950, 1740, 1700, 1675, 1630 cm⁻¹.

NMR δ (CDCl₃): 6.75 (m, 1H), 6.17 & 6.12 (2×d, J=16 Hz, 1H), 5.25 (t,J=7 Hz, 1H), 3.90 (m, 1H), 3.68 (s, 3H), 3.20 (s, 3H), 1.34 (s, 6H),0.90 (t, J=6 Hz, 1H).

Mass m/z (%): 434, 403, 362, 73.

REFERENCE EXAMPLE 33

In the method as described in Reference example 31, the same procedureswere carried out as in Reference example 31 except that3E-(4-methoxycarbonylbutylidene)-6-exo-(3-oxo-1-trans-octenyl)-7-endo-(1-methyl-1-methoxyethyloxy)-bicyclo[3.3.0]octane(35 mg, 0.081 mmol) was employed as the starting material to obtaind-3E-(4-methoxycarbonylbutylidene)-6-exo-(3-oxo-1-trans-octenyl)-7-endo-hydroxybicyclo[3.3.0]octane(26 mg, Yield: 90%). The thus obtained substance had the same spectrumdata as the compound obtained in Reference example 31.

REFERENCE EXAMPLE 34

Under argon gas atmosphere, 4-carboxybutyltriphenylphosphonium bromide(25.5 g, 57 mmol) which was previously dried at 100° C. under reducedpressure sufficiently was dissolved in 250 ml of THF. Potassiumt-butoxide (12.7 g, 114 mmol) was added thereto at room temperature.After the mixture was stirred for 5 minutes,[l-2-oxa-3-hydroxy-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]octane](5.0 g, 13.4 mmol) dissolved in THF (30 ml) was added to the mixture.After the mixture was stirred at room temperature for 30 minutes, to themixture were added a saturated aqueous ammonium chloride solution (150ml) and diethyl ether (50 ml). The resultant mixture was adjusted to pH5 with a 10% hydrochloric acid and an organic layer and an aqueous layerwas separated into respective layer. The aqueous layer was extractedwith ethyl acetate (150 ml×3 times) and all the organic layers werecombined and washed with a saturated saline solution (30 ml ×2 times).After dryness with anhydrous magensium sulfate, evaporation of thesolvent followed by dissolution of the residue in ether again.Methylation of the solution was carried out by using diazomethaneaccording to the conventional manner. Ether was distilled out therefromand the residue was purified through silica gel column chromatography(ether: n-haxane=1:1) to obtain[d-2α-(6-methoxycarbonyl-2-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1α-cyclopentanol](6.1 g, Yield: 97%).

IR (neat): 3580, 1738 cm⁻¹.

NMR δ (ppm): 5.40 (2H), 4.65 (1H), 3.65 (s, 3H), 3.20-3.80 (7H), 0.90(s, 9H), 0.10 (s, 1H).

Mass m/z (%): 470, 413, 386.

Mili-MS: 470.3092; C₂₅ H₄₆ O₆ Si=470.3062.

[α]_(D) ²⁰ =+22° (c=1.84, MeOH).

REFERENCE EXAMPLE 35

[d-2α-(6-methoxycarbonyl-2-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1α-cyclopentanol](1.29 g, 2.7 mmol) was dissolved in anhydrous methylene chloride (15 ml)and to the solution were added anhydrous sodium acetate (90 mg, 1.08mmol) and 1.16 g of celite. To the mixture was added pyridiniumchlorochromate (1.16 g, 5.4 mmol) at 0° C. while stirring, and themixture was further stirred under argon gas atmosphere at 0° C. overnight. After to the mixture was added ether (30 ml) and stirredsufficiently, the mixture was filtrated through florisil column.Evaporation of the solvent to obtain substantially pure[l-2α-(6-methoxycarbonyl-2-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentanone](1.19 g, Yield: 92%).

IR (neat): 1742 cm⁻¹.

NMR δ (ppm): 5.45 (2H), 4.70 (1H), 3.65 (s, 3H), 3.40-4.00 (5H), 0.90(s, 9H), 0.10 (6H).

Mass m/z (%): 384 (M⁺ -57), 197 (15), 196 (54), 165 (71), 164 (87), 159(21), 154 (26), 147 (20), 74 (100).

Mili-MS: 411.2219 (M⁺ -t-Bu);

M⁺ -t-Bu=C₂₁ H₃₅ O₆ Si=411.2201.

[α]_(D).sup.° =-30° (c=1.80, MeOH).

REFERENCE EXAMPLE 36

[l-2α-(6-Methoxycarbonyl-2-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentanone](100 mg, 0.21 mmol) was dissolved in 0.5 ml of anhydrous methylenechloride, and zinc-titanium tetrachloridemethylene bromide reagent(Zn-TiCl₄ -CH₂ BR₂ /THF, 1.2 ml) was added thereto at room temperature.After comfirming dissolution of the starting material by using TLC, theresultant mixture was poured into a mixed solution of a saturated sodiumhydrogencarbonate/ether (20 ml/20 ml). The mixture was stirred until anorganic layer became transparent and then the organic layer wasseparated therefrom. The separated aqueous layer was extractedsufficiently with ether (50 ml×4 times) and all the organic layers werecombined and dried with anhydrous magnesium sulfate. Evaporation of thesolvent, followed by purification through silica gel columnchromatography (hexane:ether=5:1) to obtain[l-2α-(6-methoxycarbonyl-2-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-tetrahydropyranyloxy-1-cyclopentylidene](81 mg, Yield: 91%).

IR (neat): 1745, 1660 cm⁻¹.

NMR δ (ppm): 5.40 (2H), 4.85 (2H), 4.60 (1H), 3.65 (s, 3H), 3.50-4.20(5H), 0.90 (s, 9H), 0.10 (s, 6H).

Mass m/z (%): 381 (1), 233 (10), 201 (10), 159 (25), 91 (10), 75 (100).

Mili-MS: 381.2459 (M⁺ -85);

M⁺ -85=C₂₁ H₃₇ O₄ Si=381.2459.

[α]_(D) ²⁰ =-35° (c=1.36, MeOH).

REFERENCE EXAMPLE 37

2-(6-methoxycarbonyl-2-Z-hexenyl)-3-exo-t-butyldimethylsilyloxymethyl-4-endo-tetrahydropyranyloxy-1-cyclopentylidene(17.5 mg, 0.037 mmol) was dissolved in anhydrous methylene chloride (0.6ml). Under argon gas atmosphere and at -25° C., dimethylaluminumchloride (1M hexane solution) (0.19 ml, 0.19 mmol) was added thereto,and the mixture was stirred at -25° C. for 1.5 hours. To the mixture wasadded a 25% aqueous potassium hydroxide solution (1.9 ml) and ether (3ml), and the mixture was extracted with ethyl acetate. The separatedorganic layer was washed successively with a saturated aqueous sodiumhydrogencarbonate solution and a saturated saline solution. Afterdryness with anhydrous magensium sulfate, the mixture was purifiedthrough silica gel column chromatography (hexane:ether=1:1) to obtain2-(6-methoxycarbonyl-2-Z-hexenyl)-3-exo-t-butyldimethylsilyloxymethyl-4-endo-hydroxy-1-cyclopentylidene(12.7 mg, Yield: 89%).

IR (neat): 3450, 2950, 2780, 1745, 1730 cm⁻¹.

NMR δ (ppm): 5.40 (2H), 4.80-4.95 (2H), 3.30-4.20 (4H), 3.65 (s, 3H),0.90 (s, 9H), 0.10 (s, 6H).

Mass m/z (%): 325 (23), 233 (32), 201 (40), 183 (22), 159 (27), 75(100).

Mili-MS: 325.1832 (M⁺ -57);

M⁺ -57 =C₁₇ H₂₉ O₄ Si=325.1833.

REFERENCE EXAMPLE 38

2α-(6-methoxycarbonyl-2-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-hydroxy-1-cyclopentylidene](657 mg, 1.72 mmol) was dissolved in anhydrous dimethylformamide (1.17ml), and imidazole (40 mg, 5.90 mmol) and t-butyldimethylchlorisilane(596 mg, 3.96 mmol) were added thereto. Subsequently, atmosphere in thereaction vessel was replaced with argon gas and the mixture was stirredat room temperature for 15 minutes. To the mixture was added a saturatedaqueous ammonium chloride solution and the mixture was extracted withether (25 ml×4 times). The combined extracts were washed with asaturated saline solution and dried with anhydrous magensium sulfate.Evaporation of the solvent, followed by purification through silica gelcolumn chromatography (hexane:ether=10:1) to obtain[l-2α-(6-methoxycarbonyl-2-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-t-butyldimethylsilyloxy-1-cyclopentylidene](855 mg, Yield: 100%).

IR (neat): 1745, 1660 cm⁻¹.

NMR δ (ppm): 5.45 (2H), 4.85 (2H), 4.00 (1H), 3.65 (s, 3H), 0.90 (18H),0.10 (12H).

Mass m/z (%): 439 (M³⁰ -t-Bu) (19), 233 (39), 201 (39), 189 (15), 183(18), 173 (10), 159 (22), 147 (83), 73 (100).

Mili-MS: 439.2704 (M⁺ -t-Bu);

M⁺ -t-Bu=C₂₃ H₄₄ O₄ Si₂ =439.2698.

[α]_(D) ²⁰ =-38° (c=1.36, MeOH).

REFERENCE EXAMPLE 39

Under argon gas atmosphere, 9-borabicyclo[3.3.0]nonane (dimer, 1.65 g,13.6 mmol) was suspended in THF (24 ml), and a solutio of[l-2α-(6-methoxycarbonyl-2-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-t-butyldimethylsilyloxy-1-cyclopentylidene](2.70 g, 5.4 mmol) dissolved in THF (10 ml) was added thereto at 0° C.After the mixture was stirred at 0° C. for 2 hours, a 3N aqueous sodiumhydroxide solution (5 ml) and a 30% aqueous hydroperoxide solution (5ml) was added thereto. The mixture was heated to 60° C. and stirred for1.5 hours. After almost all the THF was distilled out, to the residuewas added ether (30 ml) and adjusted to pH 5 with a 10% hydrochloricacid. The mixture was extracted with ethyl ether and the extract waswashed with a saturated aqueous sodium thiosulfate solution and asaturated saline solution and then dried with anhydrous magensiumsulfate. Evaporation of the solvent, followed by purification throughsilica gel column chromatography (hexane:ether=3:2 to 1:1) to obtain[d-1α-hydroxymethyl-2α-(6-methoxycarbonyl-2-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-t-butyldimethylsilyloxycyclopentane](1.97 g, Yield: 71%).

IR (neat): 3450, 1742 cm⁻¹.

NMR δ (ppm): 5.40 (2H), 4.15 (1H), 3.65 (s, 3H), 3.20-3.80 (5H), 0.90(18H), 0.10 (s, 6H), 0.05 (s, 6H).

Mass m/z (%): 514 (M⁺, 1.4), 233 (42), 221 (22), 219 (11), 201 (34), 189(20), 73 (100).

Mili-MS: 514.3515 (M⁺);

C₂₇ H₅₄ O₅ Si₂ =514.3506.

[α]_(D) ²⁰ =+4° (c=1.36, MeOH).

REFERENCE EXAMPLE 40

Under argon gas atmosphere,[d-1α-hydroxymethyl-2α-(6-methoxycarbonyl-2-Z-hexenyl)-3β-t-butyldimethylsilyloxymethyl-4α-t-butyldimethylsilyloxycyclopentane](1.77 g, 3.44 mmol) was dissolved in anhydrous methylene chloride (70ml), and Collins reagent (8.8 g, 34 mmol) was added thereto at 0° C.After the mixture was stirred at 0° C. for 30 minutes, 17.6 g of sodiumhydrogensulfate monohydrate was added thereto and the mixture wasdiluted with methylene chloride. The resultant mixture was returned toroom temperature and to the mixture was added ether until the wholemixture became turbid. After to the mixture was added anhydrousmagensium sulfate and stirred for 5 minutes, the mixture was filtratedthrough florisil column. By removing the solvent in the filtrate,purified[d-1α-formyl-2α-(6-methoxycarbonyl-2-Z-hyxeneyl)-3β-t-butyldimethylsilyloxymethyl-4α-t-butyldimethylsilyloxycyclopentane]was obtained (1.60 g, Yield: 91%).

IR (neat): 1750, 1730 (sh) cm⁻¹.

NMR δ (ppm): 9.85 (d, 1H), 5.35 (2H), 4.20 (1H), 3.65 (s, 3H, 3.40-3.60(2H), 2.80 (1H), 0.90 (18H), 0.10 (s, 6H), 0.05 (s, 6H).

Mass m/z (%): 497 (M⁺ -15) (1.5), 456 (16.5), 455 (M⁺ -57) (46), 363(12), 323 (12), 249 (17), 231 (21), 217 (22), 199 (43), 189 (27), 181(12), 171 (30), 73 (100).

[α]_(D) ²⁰ =+1° (c=1.00, MeOH).

EXAMPLE 28

[d-1α-Formyl-2α-(6-methoxycarbonyl-2-Z-hyxeneyl)-3β-t-butyldimethylsilyloxymethyl-4α-t-butyldimethylsilyloxycyclopentane](1.65 g, 3.22 mmol) was dissolved in anhydrous toluene (33 ml) and thesolution was charged in a sealed tube under argon gas atmosphere. Thetube was heated at 180° C. for 18 hours. After evaporation of thetoluene, the residue was purifired through silica gel columnchromatography (hexane:ether=3:1 to 1:1) to obtain[2-hydroxy-3-(4-methoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]octane](1.44 g, Yield: 87%) as scarcely colored oily products. According to thespectrum data thereof, it was confirmed that the obtained products weremixtures of 2,3-exo,exo and 2,3-endo,endo compounds.

IR (neat): 3430, 1740, 1720 (sh) cm⁻¹.

NMR δ (ppm): 5.20-6.00 (2H), 4.30 (0.4H), 3.10-4.00 (3.6H), 3.65 (s,3H), 0.90 (18H), 0.05-0.10 (12H).

Mass m/z (%): 455 (18), 437 (13), 323 (38), 249 (19), 231 (70), 218(13), 217 (68), 205 (16), 199 (59), 189 (47), 181 (14), 171 (43), 157(45), 155 (14), 147 (87), 73 (100).

EXAMPLE 29

[2-hydroxy-3-(4-methoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]octane](2,3-exo,exo and 2,3-endo,endo mixture; 12 mg, 0.023 mmol) was dissolvedin methanol (0.3 ml), and a 10% palladium carbon (3.0 mg) was addedthereto and catalytic reduction was carried out by using hydrogen gas.The reaction was followed up by a TLC of AgNO₃ -silica gel and thestarting materials were disappeared after 2 hours. The resultant mixturewas diluted with ether and palladium carbon was removed by filtrationwith the addition of Celite. Evaporation of the solvent yielded[2-hydroxy-3-(4-methoxycarbonylbutyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]octane](12 mg, Yield: 100%) as substantially colorless oily products.

IR (neat): 3450, 1742, 1725 (sh) cm⁻¹.

NMR δ (ppm): 4.30 (0.4H), 3.0-4.1 (3.6H), 3.65 (s, 3H), 0.90 (18H), 0.10(6H), 0.05 (6H).

Mass m/z (%): 457 (38), 325 (40), 233 (90), 219 (100), 201 (69).

EXAMPLE 30

In toluene (25 ml) was dissolved[2-hydroxy-3-(4-methoxycarbonyl-1-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]octane](1.11 g, 2.12 mmol). To the solution were added triethylamine (2.1 g)and methane sulfonyl chloride (2.3 g) and the mixture was stirred atroom temperature for 30 minutes.

To the mixture was added DBU (1,8-diazabicyclo[5.4.0]unde-7-cene, about3 g) and the mixture was refluxed for about 12 hours. After the reactionmixture was diluted with ether, the mixture was washed successively witha 10% aqueous hydrochloric acid solution, a saturated aqueous sodiumhydrogencarbonate solution and a saturated saline solution, and driedwith anhydrous magensium sulfate. After evaporation of the solvent, theresidue was purified through silica gel column chromatography to obtain[3-(4-methoxycarbonyl-1E-butenyl)-6-exo-t-butyl-dimethylsilyloxymethyl-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]oct-2-ene](597 mg, Yield: 57%).

IR (neat): 1745 cm⁻¹.

NMR δ (ppm): 6.25 (d, J=16 Hz, 1H), 5.30-5.70 (m, 2H), 3.70-4.10 (m,1H), 3.65 (s, 3H), 3.30-3.70 (m, 2H), 0.90 (s, 18H), 0.10 (s, 6H), 0.05(s, 6H).

Mass m/z (%): 437 (M⁺ -57).

From the spectrum data obtained above, it is identified that thestereochemistry of the di-substituted olefin is the trans form.

EXAMPLE 31

[2-hydroxy-3-(4-methoxycarbonylbutyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-t-butyl-dimethylsilyloxybicyclo[3.3.0]octane](12 mg) was dissolved in pyridine (0.5 ml), and under argon gasatmosphere, methanesulfonyl chloride (11 μl) was added thereto and themixture was stirred at room temperature. Methanesulfonyl chloride (10μl) was added thereto every 30 minutes until the strating materials weredisappeared by TLC. After confirmation of disappearance of the startingmaterials, a saturated aqueous ammonium chloride solution was addedthereto and extracted with ether. The separated organic layer was washedthree times with a saturated aqueous copper sulfate solution. Theorganic layer was dried with anhydrous magensium sulfate and then thesolvent was distilled out therefrom. The residue was dissolved intoluene (0.2 ml) and to the solution was added diazabicycloundecene (20μl) and stirred at 100° C. for 2 days under argon gas atmosphere. Theresultant mixture was cooled to room temperature and to the mixture wasadded a saturated aqueous ammonium chloride solution. The resultantmixture was extracted with ether and the separated ether layer waswashed with a saturated saline solution and then dried with anhydrousmagensium sulfate. Evaporation of the solvent, followed by purificationthrough silica gel column chromatography (hexane:ether=10:1) to obtain[l-3-(4-methoxycarbonylbutyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-t-butyldimethylsilyloxybicyclo[3.3.0]oct-2-ene](5.6 mg, Yield: 48%).

IR (neat): 1745 cm⁻¹.

NMR δ (ppm): 5.30 (1H), 3.85 (1H), 3.65 (s, 3H), 3.60 (2H), 2.90 (1H),0.90 (s, 9H), 0.85 (s, 9H), 0.05 (12H).

Mass m/z (%): 439 (M⁺ -57) (25), 243 (11), 233 (64), 207 (53), 201 (42),189 (11), 183 (21), 175 (19), 173 (14), 159 (14), 157 (14), 149 (17),148 (12), 147 (67), 73 (100).

Mili-MS: 439.2697 (M⁺ -t-Bu);

M⁺ -t-Bu=C₂₃ H₄₃ O₄ Si₂ =439.2697.

EXAMPLE 32

{l-3-(3'-Methoxycarbonyl-1'-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene}(464 mg, 1 mmol) was dissolved in THF (4.6 ml). To the thus preparedsolution was added a tetra-n-butylammonium fluoride solution (1M THFsolution, 1.5 ml), followed by stirring at room temperature for 13hours. After the solvent was distilled out under reduced pressure, tothe residue was added water, followed by extraction with ether. Theseparated ether layer was washed with a saturated saline solution, anddried with anhydrous magnesium sulfate. After the solvent was distilledout, the residue was purified through silica gel column chromatography(ether:n-hexane=1:2) to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6-exo-hydroxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene}(333 mg, Yield: 95%) as colorless oily product.

IR (neat): 3480, 1740 cm⁻¹.

NMR δ (CDCl₃): 6.26 (d, J=15 Hz, 1/3H, trans), 6.00 (d, J=12 Hz, 2/3H,cis), 5.58 (s, 1H), 5.35 (m, 1H), 4.62 (m, 1H), 3.68 (s, 3H), 3.30-4.30(m, 5H), 3.00 (m, 1H).

Mass m/z: 350, 2.66.

EXAMPLE 33

{3-(4'-Carboxy-1'-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene}(450 mg, 1 mmol) was dissolved in acetonitrile (2 ml). To the thusprepared solution were added DBU (304 mg, 2 mmol) and ethyl iodide (468mg, 3 mmol) at room temperature, followed by stirring for further 3hours. After the reaction was stopped with addition of a saturatedaqueous ammonium chloride solution, the resultant mixture was extractedwith ether. The separated ether layer was washed with a saturated salinesolution, followed by drying with anhydrous magnesium sulfate. After thesolvent was distilled out, the residue was purified through silica gelcolumn chromatography to obtain{3-(4'-ethoxycarbonyl-1'-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene(400 mg, Yield: 84%) as colorless oily product.

IR (neat); 2950, 2870, 1745, 840 cm⁻¹.

NMR δ (CDCl₃); 6.24 (d, J=16 Hz, 1/3H, trans), 5.98 (d, J=11 Hz, 2/3H,cis), 5.57 (bs, 1H), 5.30 (m, 1H), 4.60 (bs, 1H), 4.20 (q, J=7 Hz, 2H),3.20-4.20 (m, 5H), 2.95 (m, 1H), 1.30 (t, J=7 Hz, 3H), 0.90 (s, 9H).

Mass m/z; 478 (M⁺), 433, 421, 393.

{3-(4'-Ethoxycarbonyl-1'-butenyl)-6-exo-t-butyldimethylsilyloxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene}(400 mg, 0.84 mmol) was dissolved in THF (4 ml). To the thus preparedsolution was added a tetrabutylammonium fluoride (1M THF solution, 1.3ml), followed by stirring at room temperature for 12 hours. After thereaction was stopped by adding a saturated aqueous ammonium chloridesolution, THF was distilled out under reduced pressure. The resultantaqueous layer was extracted with an ether and the separated ether layerwas washed with a saturated saline solution, followed by drying withanhydrous magnesium sulfate. After the solvent was distilled out, theresidue was purified through silica gel column chromatography to obtain{3-(4'-ethoxycarbonyl-1'-butenyl)-6-exo-hydroxymethyl-7-endo-tetrahydropyranyloxybicyclo[3.3.0]oct-2-ene}(306 mg, Yield: 100%) as nearly colorless oily product.

IR (neat): 3480, 1740 cm⁻¹.

NMR δ (CDCl₃): 6.26 (d, J=15 Hz, 1/3H, trans), 6.00 (d, J=12 Hz, 2/3H,cis), 5.58 (s, 1H), 5.32 (m, 1H), 4.60 (m, 1H), 3.30-4.30 (m, 5H), 4.20(q, J=7 Hz, 2H), 3.00 (m, 1H), 1.30 (t, J=7 Hz, 3H).

Mass m/z: 364, 280.

EXAMPLE 34

Under argon gas atmosphere,{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-hydroxymethyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(stereochemistry of the double bond is E:Z=1:2) (422 mg, 1.2 mmol) andtriethylamine (0.98 ml) were dissolved in DMSO (10 ml). To the thusprepared solution was added a DMSO solution (7.5 ml) ofsulfurtrioxide-pyridine complex (575 mg, 3.6 mmol), followed by stirringat room temperature for 30 minutes. The resultant mixture was pouredinto the ice-cold water, followed by extraction with ether. Theseparated ether layer was washed with water and a saturated salinesolution. The residue was dried with anhydrous magnesium sulfate and thesolvent was distilled out to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6-(R)-formyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}.

On the other hand, sodium hydride (60% oily product, 67 mg, 1.68 mmol)was washed with an n-pentane and suspended in THF (10 ml). To the thusprepared mixture was added a THF solution (3 ml) ofdimethyl(2-oxo-3-methyl-5-heptynyl)phosphonate (418 mg, 1.8 mmol),followed by stirring at room temperature for 30 minutes. To theresultant mixture was added the above-mentioned THF solution (6 ml) of{3-(4'-methoxycarbonyl-1'-butenyl)-6(R)-formyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}.After the resultant mixture was stirred at room temperature for further1 hour, a saturated aqueous ammonium chloride solution was addedthereto. The thus prepared mixture was extracted with ether and theseparated ether layer was washed with a saturated saline solution. Theresultant mixture was dried with anhydrous magnesium sulfate and thesolvent was distilled out. The residue was purified through silica gelcolumn chromatography to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(460 mg, Yield: 84%) as colorless oily product.

IR (neat): 1740, 1695, 1680, 1625 cm⁻¹.

NMR δ (CDCl₃): 6.80 (m, 1H), 5.80-6.50 (m, 2H), 5.00-5.70 (m, 2H), 4.60(m, 1H), 3.68 (s, 3H), 1.75 (t, J=2 Hz, 3H), 1.20 (d, J=7 Hz, 3H).

Mass m/z: 454, 370, 85.

EXAMPLE 35

The reaction was carried out following the same procedure as in Example34 to synthesize{3-(4'-methoxycarbonyl-1'-butenyl)-6(R)-formyl-7(R)-tetrahydropyranyloxy(1S,5S)-cisbicyclo[3.3.0]oct-2-ene}.The thus obtained compound was reacted withdimethyl(2-oxo-4(R)-methyl-8-methyl-7-nonenyl)phosphonate (479 mg, 1.8mmol) to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(500 mg, Yield: 85%).

IR (neat): 1745, 1700, 1675, 1625 cm⁻¹.

NMR δ (CDCl₃): 6.80 (m, 1H), 5.80-6.50 (m, 2H), 4.90-5.70 (m, 3H), 4.65(m, 1H), 3.70 (s, 3H), 0.93 (d, J=6 Hz, 3H).

Mass m/z: 414, 396, 85.

EXAMPLE 36

The reaction was carried out following the same procedures as in Example34 by using{3-(4'-ethoxycarboxny-1'-butenyl)-6(S)-hydroxymethyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2ene}(437 mg, 1.2 mmol) to synthesize{3-(4'-ethoxycarbonyl-1'-butenyl)-6(R)-formyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}and finally yielded{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-5'(R)-methyl-trans-1'-decene-8'-enyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(522 mg, Yield: 85%) as colorless oily product.

IR (neat): 1745, 1695, 1680, 1625 cm⁻¹.

NMR δ (CDCl₃): 6.80 (m, 1H), 5.80-6.50 (m, 2H), 4.90-5.70 (m, 3H), 4.65(m, 1H), 4.20 (q, 2H, J=7 Hz), 1.30 (t, J=7 Hz, 3H), 0.93 (d, J=6 Hz,3H).

Mass m/z: 428, 410.

EXAMPLE 37

The reaction was carried out following the same procedures as in Example34 by using{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-hydroxymethyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(422 mg, 1.2 mmol) to synthesize{3-(4'-methoxycarbonyl-1'-butenyl)-6(R)-formyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}and finally yielded{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-trans-1'-octenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(458 mg, Yield: 86%) as colorless oily product.

IR (neat): 1740, 1680, 1625 cm⁻¹.

NMR δ (lDCl₃): 6.75 (m, 1H), 5.80-6.40 (2H), 5.00-5.70 (m, 2H), 4.60 (m,1H), 3.67 (s, 3H).

Mass m/z: 444, 360.

EXAMPLE 38

The reaction was carried out following the same procedures as in Example34 by using{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-hydroxymethyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(422 mg, 1.2 mmol) to synthesize{3-(4'-methoxycarbonyl-1'-butenyl)-6(R)-formyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}and finally yielded{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-3'-cyclopentyl-trans-1'-propenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(440 mg, Yield: 83%) as colorless oily product.

IR (neat): 1740, 1700, 1670, 1630 cm⁻¹.

NMR δ (CDCl₃): 6.80 (m, 1H), 5.80-6.50 (m, 2H), 5.00-5.70 (m, 2H), 4.60(m, 1H), 3.68 (s, 3H).

Mass m/z: 442, 411, 358.

EXAMPLE 39

The reaction was carried out following the same procedures as in Example34 by using{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-hydroxymethyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(437 mg, 1.2 mmol) to synthesize{3-(4'-ethoxycarbonyl-1'-butenyl)-6(R)-formyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}and finally yielded{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(455 mg, Yield: 81%) as colorless oily product.

IR (neat): 1740, 1694, 1678, 1625 cm⁻¹.

NMR δ (CDCl₃): 6.80 (m, 1H), 5.80-6.50 (m, 2H), 5.00-5.70 (m, 2H), 4.60(m, 1H), 4.20 (q, J=7 Hz, 2H), 1.75 (t, J=2 Hz, 3H), 1.30 (t, J=7 Hz,3H), 1.20 (d, J=7 Hz, 3H).

Mass m/z: 468, 384.

EXAMPLE 40

The reaction was carried out following the same procedures as in Example34 by using{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-hydroxymethyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(437 mg, 1.2 mmol) to synthesize{3-(4'-ethoxycarbonyl-1'-butenyl)-6(R)-formyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}and finally yielded{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-3'-cyclopentyl-trans-1'-propenyl)-7(R)-tetrahydropyranyloxy-[3.3.0]oct-2-ene}(454 mg, Yield: 83%) as colorless oily product.

IR (neat): 1740, 1700, 1670, 1630 cm⁻¹.

NMR δ (CDCl₃): 6.80 (m, 1H), 5.80-6.50 (m, 2H), 5.00-5.70 (m, 2H), 4.60(m, 1H), 4.20 (q, J=7 Hz, 2H), 1.30 (t, J=7 Hz, 3H).

Mass m/z: 456, 372.

EXAMPLE 41

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-trans-1'-octenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(73 mg, 0.16 mmol) was dissolved in methanol (2.6 ml). With addition ofsodium borohydride (6 mg, 0.16 mmol) at -25° C., the mixture was stirredat -25° C. for 40 minutes. After the reaction was stopped with additionof an acetone, a saturated aqueous ammonium chloride solution was addedto the mixture. After the methanol was distilled out, the resultantaqueous layer was extraced with ether. The separated ether layer waswashed with a saturated saline solution and dried with anhydrousmagnesium sulfate. The solvent was distilled out and the residue waspurified through silica gel column chromatography to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-trans-1'-octenyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(74 mg, Yield: 100%) as nearly colorless oily product.

IR (neat): 3470, 1745 cm⁻¹.

NMR δ (CDCl₃): 6.28 (d, =16 Hz, 1/3H, trans), 6.00 (d, J=11 Hz, 2/3H,cis), 5.10-5.75 (m, 4H), 4.67 (m, 1H), 3.70 (s, 3H).

Mass m/z: 446, 230.

EXAMPLE 42

The reaction was carried out following the same procedures as in Example41 by using{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-3'-cyclopentyl-trans-1'-propenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(130 mg, 0.29 mmol) to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'RS)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(131 mg, Yield: 100%) as colorless oily product.

IR (neat): 3500, 1742 cm⁻¹.

NMR δ (CDCl₃): 6.28 (d, J=16 Hz, 1/3H, trans), 6.00 (d, J=11 Hz, 2/3H,cis), 5.10-5.80 (m, 4H), 4.70 (m, 1H), 3.70 (s, 3H).

Mass m/z: 444, 342, 298, 220.

EXAMPLE 43

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(450 mg, 0.99 mmol) was dissolved in methanol (10 ml). With addition ofexcess amount of sodium borohydride at -25° C., the mixture was stirredat -25° C. for 1 hour. After the reaction was stopped with addition ofan acetone, a saturated aqueous ammonium chloride solution was added tothe mixture. After the methanol was distilled out, the resultant aqueouslayer was extraced with ehter. The separated ether layer was washed witha saturated saline solution and dried with anhydrous magnesium sulfate.The solvent was distilled out and the residue was purified throughsilica gel column chromatography to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(377 mg, Yield: 84%) as nearly colorless oily product.

IR (neat): 3500, 1745 cm⁻¹.

NMR δ (CDCl₃): 6.30, 6.02 (each d, J=16 Hz, J=12 Hz, 1H), 5.20-5.80 (m,4H), 4.60 (m, 1H), 3.71 (s, 3H), 1.69 (t, J=2 Hz, 3), 1.00 (m, 3H).

Mass m/z: 372, 354, 85.

EXAMPLE 44

The reaction was carried out following the same procedures as in Example43 by using{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(490 mg, 0.98 mmol) to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(492 mg, Yield: 100%) as nearly colorless oily product.

IR (neat): 3500, 1745 cm⁻¹.

NMR δ (CDCl₃): 6.26, 6.00 (each d, J=15 Hz, J=11 Hz, 1H), 5.00-5.62 (m,5H), 4.68 (m, 1H), 3.69 (s, 3H), 1.68 (s, 3H), 1.58 (s, 3H), 0.90 (d,J=6 Hz, 3H).

Mass m/z: 500, 482, 416, 85.

EXAMPLE 45

The reaction was carried out following the same procedures as in Example1 by using{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(502 mg, 0.98 mmol) to obtain{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(504 mg, Yield: 100%) as nearly colorless oily product.

IR (neat): 3500, 1745 cm⁻¹.

NMR δ (CDCl₃): 6.26, 6.00 (each d, J=15 Hz, J=11 Hz, 1H), 5.00-5.62 (m,5H), 4.68 (m, 1H), 4.20 (q, J=7 Hz, 2H), 1.30 (t, J=7 Hz, 3H), 0.93 (d,J=6 Hz, 3H).

Mass m/z: 514, 496, 430.

EXAMPLE 46

The reaction was carried out following the same procedures as in Example41 by using{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-3'-cyclopentyl-trans-1'-propenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(132 mg, 0.29 mmol) to obtain{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(133 mg, Yield: 100%) as nearly colorless oily product.

IR (neat): 3500, 1742 cm⁻¹.

NMR δ (CDCl₃): 6.28 (d, J=16 Hz, 1/3H, trans), 6.00 (d, J=11 Hz, 2/3H,cis), 5.10-5.80 (m, 4H), 4.70 (m, 1H), 4.20 (q, J=7 Hz, 2H), 1.30 (t,J=7 Hz, 3H).

Mass m/z: 458, 356.

EXAMPLE 47

The reaction was carried out following the same procedures as in Example41 by using{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'-oxo-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(136 mg, 0.29 mmol) to obtain{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2ene}(136 mg, Yield: 100%) as nearly colorless oily product.

IR (neat): 3500, 1743 cm⁻¹.

NMR δ (CDCl₃): 6.28 (d, J=16 Hz, 1/3H, trans), 6.00 (d, J=11 Hz, 2/3H,cis), 5.10-5.80 (m, 4H), 4.70 (m, 1H), 4.20 (q, J=7 Hz, 2H), 1.75 (t,J=2 Hz, 3H), 1.30 (6, J=7 Hz, 3H), 1.20 (d, J=7 Hz, 3H).

Mass m/z: 470, 368.

EXAMPLE 48

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'-(RS)-hydroxy-trans-1'-octenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(446 mg, 1 mmol) was dissolved in THF (0.16 ml). With addition of a 65%aqueous acetic acid solution (2.6 ml) thereto, the mixture was stirredat 50° C. for 2 hours. The resultant mixture was poured into a cooledsaturated aqueous sodium hydrogencarbonate solution and the mixture wasextracted with ethyl acetate. The separated organic layer was washedwith a saturated saline solution and dried with anhydrous magnesiumsulfate. The solvent was distilled out and the residue was purifiedthrough silica gel column chromatography to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(R)-hydroxy-trans-1'-octenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(119 mg, Yield: 33%) as a lower polarity component and{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-trans-1'-octenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (214 mg, Yield: 59%) as a higherpolarity component, each as colorless oily products.

Spectrum data of the higher polarity component were as follows:

IR (neat): 3400, 1742 cm⁻¹.

NMR δ (CDCl₃): 6.30 (d, J=15 Hz, 1/3H, trans), 6.02 (d, J=11 Hz, 2/3H,cis), 5.00-5.70 (m, 4H), 4.10 (m, 1H), 3.70 (s, 3H), 3.02 (m, 1H).

Mass m/z: 362, 344.

[α]_(D) ²⁰ =-35° (c=0.466, MeOH)

The spectrum data of the lower polarity component accorded with those ofthe higher polarity component.

EXAMPLE 49

The reaction was carried out following the same procedures as in Example48 by using{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(444 mg, 1 mmol) to obtain, as a lower polarity component,{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(R)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(94 mg, Yield: 26%) and, as a higher polarity component,{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(198 g, Yield: 55%), as colorless oily product, respectively.

The spectrum data of the higher polarity component were as follows:

IR (neat): 3400, 1740 cm⁻¹.

NMR δ (CDCl₃): 6.22 (d, J=15 Hz, 1/3H, trans), 5.95 (d, J=11 Hz, 2/3H,cis), 5.17-5.75 (m, 4H), 3.65 (s, 3H), 3.40-4.00 (m, 2H).

Mass m/z: 360, 342.

[α]_(D) ²⁰ =-30° (c=1.16, MeOH)

The spectrum data of the lower polarity component accorded with those ofthe higher polarity component.

EXAMPLE 50

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(350 mg, 0.77 mmol) was dissolved in THF (0.6 ml). With addition of a65% aqueous acetic acid solution (6 ml), the mixture was stirred at 50°C. for 2 hours. The resultant mixture was poured into a cooled saturatedaqueous sodium hydrogencarbonate solution and the mixture was extractedwith ethyl acetic acid ester. The organic layer was washed with asaturated saline solution and dried over anhydrous magnesium sulfate.The solvent was distilled out and the residue was purified throughsilica gel column chromatography to obtain, as a low polarity component,{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(R)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(67 mg, Yield: 23%) and, as a high polarity component,{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(143 mg, Yield: 50%), as colorless oily products, respectively.

Spectrum data of the higher polarity component were as follows:

IR (neat): 3400, 1740 cm⁻¹.

NMR δ (CDCl₃): 6.25, 6.00 (each d, J=16 Hz, J=12 Hz, 1H) 5.00-5.70 (m,3H), 3.68 (s, 3H), 1.78 (t, J=2 Hz, 3H), 0.98 (m, 3H).

Mass m/z: 372, 354, 336.

[α]_(D) ²⁰ =-16° (c=1.86, MeOH)

The spectrum data of the lower polarity component accorded with those ofthe higher polarity component.

EXAMPLE 51

The reaction was carried out following the same procedures as in Example50 by using{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-tetra-hydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(350 mg, 0.70 mmol) to obtain, as a lower polarity component,{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(R)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(99 mg, Yield: 34%) and, as a higher polarity component,{3-(4'-methoxy-carbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(126 mg, Yield: 43%), as nearly colorless oily product, respectively.

The spectrum data of the higher polarity component were as follows:

IR (neat): 3400, 1740 cm⁻¹.

NMR δ (CDCl₃): 6.25, 6.00 (each D, d=15 Hz, J=12 Hz, 1H), 5.10-5.80 (m,5H), 3.70 (s, 3H), 1.70 (s, 3H), 1.62 (s, 3H), 0.95 (d, J=6 Hz, 3H).

Mass m/z: 416, 398, 380.

[α]_(D) ²⁰ =-31° (c=2.29, MeOH)

The spectrum data of the lower polarity component accorded with those ofthe higher polarity component.

EXAMPLE 52

The reaction was carried out following the same procedures as in Example50 by using{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(504 mg, 0.98 mmol) to obtain, as a lower polarity component,{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(R)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(139 mg, Yield: 33%) and, as a higher polarity component,{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(194 mg, Yield: 46%), as colorless oily products, respectively.

Spectrum data of the higher polarity component were as follows:

IR (neat): 3400, 1740 cm⁻¹.

NMR δ (CDCl₃): 6.25, 6.00 (each d, J=15 Hz, J=12 Hz, 1H), 5.10-5.80 (m,5H), 4.20 (q, J=7 Hz, 2H), 170 (s, 3H), 1.62 (s, 3H), 1.30 (t, J=7 Hz,3H), 0.95 (d, J=6 Hz, 3H).

Mass m/z: 430, 412, 394.

EXAMPLE 53

The reaction was carried out following the same procedures as in Example48 by using{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(458 mg, 1 mmol) to obtain, as a lower polarity component,{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(R)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(75 mg, Yield: 20%), and, as a higher polarity component,{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(199 mg, Yield: 53%), as colorless and viscous oily products,respectively.

The spectrum data of the higher polarity component were as follows:

IR (neat): 3400, 1740 cm⁻¹.

NMR δ (CDCl₃): 6.22 (d, J=15 Hz, 1/3H, trans), 5.95 (d, J=11 Hz, 2/3H,cis), 5.17-5.75 (m, 4H), 4.20 (q, J=7 Hz, 2H), 3.40-4.00 (m, 2H), 1.30(t, J=7 Hz, 3H).

Mass m/z: 374, 356.

The spectrum data of the lower polarity component accorded with those ofthe higher polarity component.

EXAMPLE 54

The reaction was carried out following the same procedures as in Example48 by using(3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(RS)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(470 mg, 1 mmol) to obtain as a lower polarity component,{3-(4'-ethoxy-carbonyl-1'-butenyl)-6(S)-(3'(R)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(81 mg, Yield: 21%) and, as a higher polarity component,{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(201 mg, Yield: 52%), as colorless oily products, respectively.

The spectrum data of the higher polarity component were as follows:

IR (neat): 3400, 1740 cm⁻¹.

NMR δ (CDCl₃): 6.22 (d, J=15 Hz, 1/3H, trans), 5.95 (d, J=11 Hz, 2/3H,cis), 5.17-5.75 l (m, 4H), 4.20 (q, J=7 Hz, 2H), 3.40-4.00 (m, 2H), 1.75(t, J=2 Hz, 3H), 1.30 (t, J=7 Hz), 1.20 (d, J=7 Hz, 3H).

Mass m/z: 386, 368.

The spectrum data of the lower polarity component accorded with those ofthe higher polarity component.

EXAMPLE 55

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-trans-1'-octenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(362 mg, 1 mmol) was dissolved in DMF (1.5 ml). With addition ofimidazole (204 mg, 3 mmol) and t-butyldimethylsilyl chloride (452 mg, 3mmol), the resultant mixture was stirred at room temperature for 10hours. The reaction was stopped by adding a saturated aqueous ammoniumchloride solution and the mixture was extracted with ether. Theseparated ether layer was washed with a saturated saline solution anddried with anhydrous magnesium sulfate. The solvent was distilled outand the residue was purified through silica gel column chromatography toobtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-t-butyldimethylsilyloxy-trans-1'-octenyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(590 mg, Yield: 100%) as nearly colorless oily product.

IR (neat): 1750, 840 cm⁻¹.

NMR δ (CDCl₃): 6.27 (d, J=16 Hz, 1/3H, trans), 6.02 (d, J=11 Hz, 2/3H,cis), 5.51 (m, 4H), 4.07 (m, 1H), 3.70 (m, 1H), 3.69 (s, 3H).

Mass m/z: 590, 534, 533, 519.

[α]_(D) ²⁰ =-37° (c=0.61, CHCl₃).

EXAMPLE 56

The reaction was carried out following the same procedures as in Example55 by using{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(360 mg, 1 mmol) to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(586 mg, Yield: 100%) as nearly colorless oily products.

IR (neat): 1745, 835 cm⁻¹.

NMR δ (CDCl₃): 6.25 (d, J=16 Hz, 1/3H, trans), 6.01 (d, J=11 Hz, 2/3H,cis), 5.50 (m, 4H), 4.07 (m, 1H), 3.69 (m, 1H), 3.68 (s, 3H).

Mass m/z: 588, 532, 531, 517.

[α]_(D) ²⁰ =-37° (c=1.62, CHCl₃).

EXAMPLE 57

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(70 mg, 0.19 mmol) was dissolved in DMF (0.25 ml). With addition oft-butyldimethylsilylchloride (85 mg, 0.57 mmol) and imidazole (38 mg,0.57 mmol), the mixture was stirred at room temperature for 2 hours. Thereaction was stopped by adding a saturated aqueous ammonium chloridesolution and the mixture was extracted with ether. The separated etherlayer was washed with a saturated saline solution and dried withanhydrous magnesium sulfate. The solvent was distilled out and theresidue was purified through silica gel column chromatography to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-t-butyldimethylsilyloxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(93 mg, Yield: 82%) as nearly colorless oily products.

IR (neat): 1745, 840 cm⁻¹.

NMR δ (CDCl₃): 6.23, 5.97 (each d, J=15 Hz, J=11 Hz, 1H), 5.05-5.70 (m,4H), 3.65 (s, 3H), 1.75 (t, J=2 Hz, 3H).

Mass m/z: 600, 543.

[α]_(D) ²⁰ =-30° (c=1.82, CHCl₃).

EXAMPLE 58

The reaction was carried out following the same procedures as in Example57 by using{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(90 mg, 0.22 mmol) to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-t-butyldimethylsilyloxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(108 mg, Yield: 78%) as nearly colorless oily products.

IR (neat): 1745, 835 cm⁻¹.

NMR δ (CDCl₃): 6.20, 5.95 (each d, J=15 Hz, J=11 Hz, 1H), 5.00-5.60 (m,5H), 3.68 (s, 3H), 1.66 (s, 3H), 1.60 (s, 3H).

Mass m/z: 644, 587, 519.

[α]_(D) ²⁰ =-45° (c=2.18, CHCl₃).

EXAMPLE 59

The reaction was carried out following the same procedures as in Example57 by using{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(95 mg, 0.22 mmol) to obtain{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-t-butyldimethylsilyloxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(145 mg, Yield: 100%) as nearly colorless oily products.

IR (neat): 1743 cm⁻¹.

NMR δ (CDCl₃): 6.20, 5.95 (each d, J=15 Hz, J=11 Hz, 1H), 5.00-5.60 (m,5H), 4.20 (q, J=7 Hz, 2H), 1.66 (s, 3H), 1.60 (s, 3H), 1.30 (t, J=7 Hz,3H).

Mass m/z: 658, 601, 533.

EXAMPLE 60

The reaction was carried out following the same procedures as in Example55 by using{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(187 mg, 0.5 mmol) to obtain{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(286 mg, Yield: 95%) as colorless oily products.

IR (neat): 1745 cm⁻¹.

NMR δ (CDCl₃): 6.25 (d, J=16 Hz, 1/3H, trans), 6.01 (d, J=11 Hz, 2/3H,cis), 5.50 (m, 4H), 4.20 (q, J=7 Hz, 2H), 4.07 (m, 1H), 3.60 (m, 1H),1.30 (t, J=7 Hz, 3H).

Mass m/z: 602, 545.

EXAMPLE 61

The reaction was carried out following the same procedures as in Example55 by using{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(193 mg, 0.5 mmol) to obtain{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-t-butyldimethylsilyloxy-4'-(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(300 mg, Yield: 100%) as nearly colorless oily products.

IR (neat): 1745 cm⁻¹.

NMR δ (CDCl₃): 6.25 (d, J=16 Hz, 1/3H, trans), 6.01 (d, J=11 Hz, 2/3H,cis), 5.50 (m, 4H), 4.20 (q, J=7 Hz, 2H), 4.07 (m, 1H), 3.69 (m, 1H),1.75 (t, J=2 Hz, 3H), 1.30 (t, J=7 Hz, 3H), 1.20 (d, J=7 Hz, 3H).

Mass m/z: 614, 557.

EXAMPLE 62

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-trans-1'-octenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(362 mg, 1 mmol) was dissolved in methylene chloride (3.6 ml).Dihydropryrane (840 mg, 10 mmol) was added to the resultant solution andcatalytic amount of p-toluenesulfonic acid was further added to themixture, followed by stirring at room temperature for 10 minutes. Thereaction was stopped by addition of a saturated aqueous sodiumhydrogencarbonate solution and the mixture was extracted with ether. Theseparated ether layer was washed with a saturated saline solution,followed by dryness with anhydrous magnesium sulfate. After the solventwas distilled out, the residue was purified through silica gel columnchromatography to obtain{3-(4-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-tetrahydropyranyloxy-trans-1'-octenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(447 mg, Yield: 90%) as nearly colorless oily products.

IR (neat): 1745 cm⁻¹.

NMR δ (CDCl₃): 6.25 (d, J=16 Hz, 1/3H, trans), 6.02 (d, J=11 Hz, 2/3H,cis), 5.50 (m, 4H), 4.60 (m, 2H), 4.05 (m, 1H), 3.69 (s, 3H), 3.40-4.00(m, 5H),

Mass m/z: 530, 446.

EXAMPLE 63

The reaction was carried out following the same procedures as in Example62 by using{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(360 mg, 1 mmol) to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(475 mg, Yield: 90%) as colorless oily products.

IR (neat): 1745 cm⁻¹.

NMR δ (CDCl₃): 6.23 (d, J=16 Hz, 1/3H, trans), 6.03 (d, J=11 Hz, 2/3H,cis), 5.50 (m, 4H), 4.60 (m, 2H), 4.05 (m, 1H), 3.68 (s, 3H), 3.40-4.00(m, 5H).

Mass m/z: 528, 444.

EXAMPLE 64

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(186 mg, 0.5 mmol) was dissolved in methylene chloride (1.86 ml).Dihydropyrane (420 mg, 5 mmol) was added to the resultant solution andcatalytic amount of p-toluenesulfonic acid was further added to themixture, followed by stirring at room temperature for 10 minutes. Thereaction was stopped by addition of a saturated aqueous sodiumhydrogencarbonate solution and the mixture was extracted with ether. Theseparated ether layer was washed with a saturated saline solution,followed by dryness with anhydrous magnesium sulfate. After the solventwas distilled out, the residue was purified through silica gel columnchromatography to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-tetrahydropyranyloxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(256 mg, Yield: 95%) as nearly colorless oily products.

IR (neat): 1743 cm⁻¹.

NMR δ (CDCl₃): 6.23 (d, J=16 Hz, 1/3H, trans), 6.03, (d, J=11 Hz, 2/3H,cis), 5.50 (m, 4H), 4.60 (m, 2H), 4.05 (m, 1H), 3.67 (s, 3H), 3.40-4.00(m, 5H), 1.75 (t, J=2 Hz, 3H), 1.20 (d, J=7 Hz, 3H).

Mass m/z: 538, 454.

EXAMPLE 65

The reaction was carried out following the same procedure as in Example64 by using{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(208 mg, 0.5 mmol) to obtain{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-tetrahydropyranyloxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(274 mg, Yield: 94%) as nearly colorless oily products.

IR (neat): 1745 cm⁻¹.

NMR δ (CDCl₃): 6.26, 6.00 (each d, J=15 Hz, J=11 Hz, 1H), 5.00-5.62 (m,5H), 4.65 (2H, m), 3.70 (s, 3H), 0.93 (d, J=6 Hz, 3H).

Mass m/z: 582, 498.

EXAMPLE 66

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(54 mg, 0.145 mmol) was dissolved in methanol (1.16 ml). A 10% aqueoussodium hydroxide solution (1.16 ml) was added to the thus preparedmixture at 0° C., followed by stirring at 0° C. for 8 hours. Thereaction mixture was diluted with ether, followed by neutralization witha 10% aqueous hydrochloric acid solution under ice-cooling. Then,methanol was distilled out under reduced pressure. The resultant aqueouslayer was adjusted to pH 3 to 4 and extracted with ethyl acetate. Afterthe separated ether layer was dried with anhydrous magensium sulfate,the solvent was distilled out to obtain{3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(50 mg, Yield: 96%).

IR (neat): 3350, 2950, 1715 cm⁻¹.

NMR δ (CDCl₃): 6.32 (d, J=16 Hz, 1/3H, trans), 6.04 (d, J=11 Hz, 2/3H,cis), 5.20-5.90 (m, 4H), 1.81 (t, J=2 Hz, 3H), 1.00 (m, 3H).

EXAMPLE 67

{3-(4'-Methoxycarbony-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octene}(40 mg, 0.086 mmol) was dissolved in methanol (0.69 ml). A 10% aqueoussodium hydroxide solution (1.16 ml) was added to the thus preparedsolution at 0° C., followed by stirring at 0° C. for 8 hours. Theresultant mixture was diluted with ether, and neutralized with a 10%aqueous hydrochloric acid solution under ice-cooling. After methanol wasdistilled out under reduced pressure, the resultant aqueous layer wasadjusted to pH 3 to 4 and extracted with ethyl acetate. The separatedorganic layer was dried with anhydrous magnesium sulfate and the solventwas distilled out to obtain{3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene} (37 mg, Yield: 95%).

IR (neat): 3350, 2950, 1715 cm⁻¹.

NMR δ (CDCl₃): 6.30 (d, J=16 Hz, 1/3H, trns) 6.02 (d, J=11 Hz, 2/3H,cis), 5.28-5.75 (m, 4H), 5.12 (t, J=7 Hz, 1H), 1.61 (s, 3H), 1.68 (s,3H), 0.93 (d, J=6 Hz, 3H).

REFERENCE EXAMPLE 41

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-trans-1'-propenyl-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(cis:trans=2:1 mixture; 105 mg, 0.18 mmol) andmethylbenzoatetricarbonylchromium (9 mg, 0.03 mmol) were dissolved inacetone (10 ml), and degassed. In autoclave under 70 Kg/cm² of hydrogengas pressure, the reaction was carried out at 120° C. for 15 hours. Thesolvent was distilled out and the residue was purified through silicagel column chromatograpy to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(105 mg, Yield: 100%) as nearly colorless oily products.

IR (neat): 1745 cm⁻¹.

NMR δ (CDCl₃): 5.50 (m, 2H), 5.23 (t, J=7 Hz, 1H), 3.68 (s, 3H),3.50-4.00 (m, 2H).

Mass m/z: 533, 521.

Results are summarized in the following Table 6 in which solvents andcatalysts other than the above-mentioned were used.

                                      TABLE 6                                     __________________________________________________________________________                 Amount of                                                                           Hydrogen                                                                catalyst                                                                            pressure                                                                            Temperature                                                                          Reaction                                                                            Yield                                   Solvent                                                                            Catalyst                                                                              (wt. %)                                                                             (Kg/cm.sup.2)                                                                       (°C.)                                                                         time (hour)                                                                         (%)                                     __________________________________________________________________________    acetone                                                                            toluene-                                                                              20    70    130    13    82*                                          tricarbonyl-                                                                  chromium                                                                 aceto-                                                                             methylbezo-                                                                           20    70    130    12    21*                                     nitrile                                                                            atetricarbo-                                                                  nylchromium                                                              acetone                                                                            mesitylene-                                                                           20    70    100    12    52*                                          tricarbonyl-                                                                  molybdenum                                                               acetone                                                                            mesitylene-                                                                           20    70    120    12    12*                                          tricarbonyl-                                                                  tungsten                                                                 acetone                                                                            triphenyl-                                                                            20    70    180    15     9*                                          phosphin-                                                                     pentacarbonyl-                                                                chromium                                                                 acetone                                                                            Hydridecyclo-                                                                         10    90    100    15    50*                                          pentadienyl-                                                                  tricarbonyl-                                                                  chromium                                                                 __________________________________________________________________________     *Selectivity coefficient of EIsomer was 100%.                            

REFERENCE EXAMPLE 42

The reaction was carried out following the same procedures as inReference example 41 by using{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-trans-1'-propenyl-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(cis:trans=2:1 mixture; 111 mg, 0.21 mmol) to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(100 mg, Yield: 90%) as nearly colorless oily product.

IR (neat): 1744 cm⁻¹.

NMR δ (CDCl₃): 5.48 (m, 2H), 5.23 (t, J=7 Hz, 1H), 4.60 (m, 2H), 3.68(s, 3H), 3.40-4.00 (m, 6H).

Mass m/z: 530, 461, 446.

REFERENCE EXAMPLE 43

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'-(S)-t-butyldimethylsilyloxy-trans-1'-octenyl-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]-oct-2-ene}(cis:trans=2:1 mixture; 107 mg, 0.18 mmol) andmethylbezoatetricarbonylchromium (9 mg, 0.03 mmol) were dissolved inacetone (10 ml), and degassed. In autoclave under 70 Kg/cm² of hydrogengas pressure, the reaction was carried out at 120° C. for 15 hours. Thesolvent was distilled out and the residue was purified through silicagel column chromatography to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-t-butyldimethylsilyloxy-trans-1'-octenyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(107 mg, 100%) as nearly colorless oily products.

IR (neat): 1745 cm⁻¹.

NMR δ (CDCl₃): 5.50 (m, 2H), 5.23 (t, J=7 Hz, 1H), 3.68 (s, 3H),3.50-4.00 (m, 2H).

Mass m/z: 535.

REFERENCE EXAMPLE 44

The reaction was carried out following the same procedures as inReference example 43 by using{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-tetrahydropyranyloxy-trans-1'-octenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(cis:trans=2:1 mixture; 112 mg, 0.21 mmol) to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-tetrahydropyranyloxy-trans-1'-octenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(101 mg, Yield: 90%) as nearly colorless oil products.

IR (neat): 1744 cm⁻¹.

NMR δ (CDCl₃): 5.48 (m, 2H), 5.23 (t, J=7 Hz, 1H), 4.60 (m, 2H), 3.68(s, 3H), 3.40-4.00 (m, 6H).

Mass m/z: 532, 448.

REFERENCE EXAMPLE 45

{3-(4'-Ethoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-trans-1'-propenyl-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(cis:trans=2:1 mixture; 108 mg, 0.18 mmol) andmethylbezoatetricarbonylchromium (9 mg, 0.03 mmol) were dissolved inacetone (10 ml), and degassed. In autoclave under 70 Kg/cm² of hydrogenpressure, the reaction was carried out at 120° C. for 15 hours. Thesolvent was distilled out and the residue was purified through silicagel column chromatography to obtain{3(E)-(4'-ethoxycarbonylbutylidene)-6(S)-(3'(S)-t-butyldimethylsilyloxy-3'-cyclpentyl-trans-1'-propenyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(108 mg, Yield: 100%) as nearly colorless oily product.

IR (neat): 1745 cm⁻¹.

NMR δ (CDCl₃): 5.50 (m, 2H), 5.23 (t, J=7 Hz, 1H), 4.20 (q, J=7 Hz, 2H),3.50-4.00 (m, 2H), 1.30 (t, J=7 Hz, 3H).

Mass m/z: 604, 547, 535.

REFERENCE EXAMPLE 46

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-t-butyldimethylsilyloxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]-oct-2-ene}(cis:trans=2:1 mixture; 116 mg, 0.18 mmol) andmethylbezoatetricarbonylchromium (9 mg, 0.03 mmol) were dissolved inacetone (10 ml), and degassed. In autoclave under 70 Kg/cm² of hydrogenpressure, the reaction was carried out at 120° C. for 15 hours. Thesolvent was distilled out and the residue was purified through silicagel column chromatography to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-t-butyldimethylsilyloxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(105 mg, Yield: 90%) as nearly colorless oily product.

IR (neat): 1745 cm⁻¹.

NMR δ (CDCl₃): 5.50 (m, 2H), 5.18 (m, 2H), 3.70 (s, 3H), 1.74 (s, 3H),1.62 (s, 3H).

Mass m/z: 646, 589.

REFERENCE EXAMPLE 47

The reaction was carried out following the same procedures as inReference example 46 by using{3-(4'-etoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-t-butyldimethylsilyloxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(cis:trans=2:1 mixture; 118 mg, 0.18 mmol) to obtain{3(E)-(4'-ethoxycarbonylbutylidene)-6(S)-(3'(S)-t-butyldimethylsilyloxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(107 mg, Yield: 90%) as nearly colorless oily product.

IR (neat): 1745 cm⁻¹.

NMR δ (CDCl₃): 5.50 (m, 2H), 5.23 (m, 2H), 4.20 (q, J=7 Hz, 2H), 1.70(s, 3H), 1.62 (s, 3H), 1.30 (t, J=7 Hz, 3H).

Mass m/z: 660, 503.

REFERENCE EXAMPLE 48

The reaction was carried out following the same procedures as inReference example 6 by using{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-tetrahydropyranyloxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo-[3.3.0]-oct-2-ene}(cis-trans=2:1 mixture; 105 mg, 0.18 mmol) to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-tetrahydropyranyloxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(89 mg, Yield: 85%) as nearly colorless oil product.

IR (neat): 1743 cm⁻¹.

NMR δ (CDCl₃): 5.50 (m, 2H), 5.21 (m, 2H), 4.60 (m, 2H), 3.66 (s, 3H),3.30-4.10 (m, 6H), 0.93 (d, J=6 Hz, 3H).

Mass m/z: 584, 500.

REFERENCE EXAMPLE 49

{3-(4'-Methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-t-butyldimethylsilyloxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(cis:trans=2:1 mixture; 92 mg, 0.16 mmol) andmethylbezoatetricarbonylchromium (9 mg, 0.03 mmol) were dissolved inacetone (10 ml), and degassed. In autoclave under 70 Kg/cm² of hydrogengas pressure, the reaction was carried out at 120° C. for 15 hours. Thesolvent was distilled out and the residue was purified through silicagel column chromatography to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-t-butyldimethylsilyloxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]-octane}(38 mg, Yield: 41%) as nearly colorless oily product.

IR (neat): 1745 cm⁻¹.

NMR δ (CDCl₃): 5.45 (m, 2H), 5.20 (t, J=7 Hz, 1H), 3.62 (s, 3H), 1.74(t, J=2 Hz, 3H).

Mass m/z: 602, 545.

Results are summarized in the following Table 7 in which solvents andcatalysts other than the above-mentioned were used.

                                      TABLE 7                                     __________________________________________________________________________                 Amount of                                                                           Hydrogen                                                                catalyst                                                                            pressure                                                                            Temperature                                                                          Reaction                                                                            Yield                                   Solvent                                                                            Catalyst                                                                              (wt. %)                                                                             (Kg/cm.sup.2)                                                                       (°C.)                                                                         time (hour)                                                                         (%)                                     __________________________________________________________________________    acetone                                                                            toluene-                                                                              20    70    130    13    31*                                          tricarbonyl-                                                                  chromium                                                                 aceto-                                                                             methylbezo                                                                            20    70    130    12     5*                                     nitrile                                                                            atetricarbo-                                                                  nylchromium                                                              acetone                                                                            mesitylene-                                                                           20    70    100    12    26*                                          tricarbonyl-                                                                  molybdenum                                                               acetone                                                                            mesitylene-                                                                           20    70    120    12     5*                                          tricarbonyl-                                                                  tungsten                                                                 acetone                                                                            triphenyl-                                                                            20    70    180    15     4*                                          phosphin-                                                                     pentacarbonyl-                                                                chromium                                                                 acetone                                                                            Hydridecyclo-                                                                         10    90    100    15    21*                                          pentadienyl-                                                                  tricarbonyl-                                                                  chromium                                                                 __________________________________________________________________________     *Selectivity coefficient of EIsomer was 100%.                            

REFERENCE EXAMPLE 50

The reaction was carried out following the same procedures as inReference example 49 by using{3-(4'-methoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-tetrahydropyranyloxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(cis:trans=2:1 mixture; 86 mg, 0.16 mmol) to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-tetrahydropyranyloxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(26 mg, Yield: 30%) as nearly colorless oily product.

IR (neat): 1745 cm⁻¹.

NMR δ (CDCl₃): 5.48 (m, 2H), 5.23 (t, J=7 Hz, 1H), 4.60 (m, 2H), 3.70(s, 3H), 1.75 (t, J=2 Hz, 3H).

Mass m/z: 540, 456.

REFERENCE EXAMPLE 51

The reaction was carried out following the same procedures as inReference example 49 by using{3-(4'-ethoxycarbonyl-1'-butenyl)-6(S)-(3'(S)-butyldimethylsilyloxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(cis:trans=2:1 mixture; 98 mg, 0.16 mmol) to obtain{3(E)-(4'-ethoxycarbonylbutylidene)-6(S)-(3'(S)-t-butyldimethylsylyloxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-t-butyldimethylsylyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(39 mg, Yield: 40%) as nearly colorless oily product.

IR (neat): 1745 cm⁻¹.

NMR δ (CDCl₃): 5.48 (m, 2H), 5.23 (t, J=7 Hz, 1H), 4.20 (q, J=7 Hz, 2H),1.75 (t, J=2 Hz, 3H), 1.30 (t, J=7 Hz, 3H).

Mass m/z: 616, 559.

REFERENCE EXAMPLE 52

The reaction was carried out following the same procedures as inReference example 49 by using{3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(cis:trans=2:1 mixture; 36 mg, 0.100 mmol) to obtain{3(E)-(4'-carboxybutylidene)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(6 mg, Yield: 18%) as viscous colorless oily products.

IR (Neat): 3350, 1710 cm⁻¹.

NMR δ (CDCl₃): 5.47 (m, 2H), 5.18 (t, J=7 Hz, 1H), 3.50-4.09 (m, 2H),1.78 (m, 3H), 0.94 and 1.02 (d, J=6.5 Hz, 3H).

Mass m/z: 360, 342, 324.

The thus obtained product agreed with useful carbacyclin analogsdisclosed in "Angew. Chem. Int. Ed. Engl., 20, 1046 (1981)" by H.Vorbruggen et al.

REFERENCE EXAMPLE 53

The reaction was carried out following the same procedures as inReference example 46 by using{3-(4'-carboxy-1'-butenyl)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]oct-2-ene}(20 mg, 0.05 mmol) (cis:trans=2:1 mixture) to obtain{3(E)-(4'-carboxybutylidene)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(14 mg, Yield: 68%) as viscous colorless oily products.

IR (neat): 3400, 1710 cm⁻¹.

NMR δ (CDCl₃): 5.50 (m, 2H), 5.20-5.30 (m, 2H), 4.14 (m, 1H), 3.70 (m,1H), 1.70 (s, 3H), 1.62 (s, 3H), 0.95 (d, J=6 Hz, 3H).

Mass m/z: 404, 386, 368.

The thus obtained product is a carbacyclin analog. The usefulnessthereof was published in '83 Inflammation Seminar--Prostaglandin ProgramPreliminary Text, Shinsaku Kobayashi, p. 37.

REFERENCE EXAMPLE 54

{3(E)-(4'-Methoxycarbonylbutylidene)-6(S)-(3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(93 mg, 0.16 mmol) was dissolved in THF (1.5 ml). A THF solution oftetrabutylammonium fluoride (0.48 mmol, 1M THF solution) was added tothe thus prepared mixture, followed by stirring at room temperature for12 hours. A saturated saline solution was added to the mixture and themixture was extracted with ethyl acetate. After the separated organiclayer was dried with anhydrous magnesium sulfite. The solvent wasdistilled out and the residue was purified through silica gel columnchromatography to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(47 mg, Yield: 82%) as colorless viscous liquid. The product solifiedwhen allowed to stand.

IR (neat): 3400, 1742 cm⁻¹.

NMR δ (CDCl₃): 5.50 (m, 2H), 5.20 (t, J=7 Hz, 1H), 3.67 (s, 3H),3.50-3.90 (m, 2H).

Mass m/z: 344, 326.

REFERENCE EXAMPLE 55

{3(E)-(4'-Methoxycarbonylbutylidene)-6(S)-(3'(S)-tetrahydropyranyloxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(53 mg, 0.1 mmol) was dissolved in THF (0.13 ml). A 65% aqueous aceticacid solution (1.3 ml) was added to the thus prepared solution, followedby stirring at 50° C. for 2 hours. The mixture was poured into a cooledsaturated aqueous sodium hydrogencarbonate solution, and the mixture wasextracted with ethyl acetate. After the separated organic layer wasdried with anhydrous magnesium sulfite and the solvent was distilledout, the residue was purified through silica gel column chromatographyto obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(33 mg, Yield: 90%) as colorless viscous liquid. The products solidifiedwhen allowed to stand. Each spectrum data accorded completely with thoseobtained in Reference Example 54.

REFERENCE EXAMPLE 56

The reaction was carried out following the same procedures as inReference example 54 by using{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-t-butyldimethylsilyloxy-trans-1'-octenyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-trans-1'-octenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(52 mg, Yield: 90%) as nearly colorless viscous oily product.

IR (neat): 3370, 1740 cm⁻¹.

NMR δ (CDCl₃): 5.49 (m, 2H), 5.23 (t, J=7 Hz, 1H), 3.66 (s, 3H),3.55-4.05 (m, 2H).

Mass m/z: 346, 328.

The above values completely accorded with those described in theReference (M. Hayashi, et al., Tetrahedron, 37, 4391 (1981)). In theabove-mentioned reference,{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-trans-1'-octenyl)-7(R)-hydroxy-cis-bicyclo[3.3.0]octene}was led to carbacycline.

REFERENCE EXAMPLE 57

The reaction was carried out following the same procedures as inReference example 55 by using{3(E)-4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-tetrahydropyranyloxy-trans-1'-octenyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(54 mg, 0.1 mmol) to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-trans-1'-octenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(34 mg, Yield: 90%) as nearly colorless viscous oily product. Eachspectrum data completely accorded with those obtained in Referenceexample 56.

REFERENCE EXAMPLE 58

The reaction was carried out following the same procedures as inReference example 54 by using{3(E)-(4'-ethoxycarbonylbutylidene)-6(S)-(3'(S)-t-butyldimethylsilyloxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(60 mg, 0.1 mmol) to obtain{3(E)-(4'-ethoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(36 mg, Yield: 100%) as colorless viscous oily product. The productsolidified when allowed to stand.

IR (neat): 3400, 1742 cm⁻¹.

NMR δ (CDCl₃): 5.50 (m, 2H), 5.20 (t, J=7 Hz, 1H), 4.20 (q, J=7 Hz, 2H),3.50-3.95 (m, 2H), 1.30 (t, J=7 Hz, 3H).

Mass m/z: 358, 340.

REFERENCE EXAMPLE 59

The reaction was carried out following the same procedures as inReference example 54 by using{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-t-butyldimethylsilyloxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(103 mg, 0.16 mmol) to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(60 mg, Yield: 90%) as nearly colorless oily product.

IR (neat): 3400, 1742 cm⁻¹.

NMR δ (CDCl₃): 5.50 (m, 2H), 5.20 (m, 2H), 3.67 (s, 3H), 3.50-3.90 (m,2H), 0.93 (d, J=6 Hz, 3H).

Mass m/z: 418, 400, 382.

REFERENCE EXAMPLE 60

The reaction was carried out following the same procedures as inReference example 59 by using{3(E)-(4'-ethoxycarbonylbutylidene)-6(S)-(3'(S)-t-butyldimethylsilyloxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-bicyclo[3.3.0]octane}(66 mg, 0.1 mmol) to obtain{3(E)-(4'-ethoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(43 mg, Yield: 100%) as nearly colorless oily products.

IR (neat): 3400, 1742 cm⁻¹.

NMR δ (CDCl₃): 5.50 (m, 2H), 5.20 (m, 2H), 4.20 (q, J=7 Hz, 2H),3.50-3.90 (m, 2H), 1.30 (t, J=7 Hz, 3H), 0.93 (d, J=6 Hz, 3H).

Mass m/z: 430, 412, 394.

REFERENCE EXAMPLE 61

The reaction was carried out following the same procedures as inReference example 55 by using{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-tetrahydropyranyloxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(93 mg, 0.16 mmol) to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(60 mg, Yield: 90%) as nearly colorless oily product.

Each spectrum data completely accorded with those obtained in Referenceexample 59.

REFERENCE EXAMPLE 62

The reaction was carried out following the same procedures as inReference example 54 by using{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-t-butyldimethylsilyloxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(120 mg, 2 mmol) to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(71 mg, 95%) as nearly colorless oily product.

IR (neat): 3400, 1742 cm⁻¹.

NMR δ (CDCl₃): 5.50 (m, 2H), 5.20 (t, J=7 Hz, 1H), 3.67 (s, 3H), 1.75(t, J=2 Hz, 3H), 1.20 (d, J=7 Hz, 3H).

Mass m/z: 374, 356.

REFERENCE EXAMPLE 63

The reaction was carried out following the same procedures as inReference example 55 by using{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-tetrahydropyranyloxy-4'(RS)-methyl-trans-1'l-octen-6'-ynyl)-7(R)-tetrahydropyranyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}54 mg, 0.1 mmol) to obtain{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(37 mg, Yield: 100%) as nearly colorless oily product. Each spectrumdata completely accorded with those obtained in Reference example 62.

REFERENCE EXAMPLE 64

The reaction was carried out following the same procedures as inReference Example 54 by using{3-(E)-(4'-ethoxycarbonylbutylidene)-6(S)-(3'(S)-t-butyldimethylsilyloxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-t-butyldimethylsilyloxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(62 mg, 0.1 mmol) to obtain{3(E)-(4'-ethoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo-[3.3.0]octane}(39 mg, Yield: 100%) as nearly colorless oily product.

IR (neat): 3400, 1742 cm⁻¹.

NMR δ (CDCl₃): 5.50 (m, 2H), 5.20 (t, J=7 Hz, 1H), 4.20 (q, J=2 Hz, 3H),1.75 (t, J=2 Hz, 3H), 1.30 (t, J=7 Hz, 3H), 1.20 (d, J=7 Hz, 3H).

Mass m/z: 388, 370.

REFERENCE EXAMPLE 65

{3(E)-(4'-Methoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(45 mg, 0.12 mmol) was dissolved in methanol (1 ml). A 10% aqueoussodium hydroxide solution (0.5 ml) was added to the thus preparedsolution, followed by stirring at 0° C. for 13 hours. The reactionmixture was diluted with ether, and neutralized with a 10% aqueoushydrochloric acid solution. Then, methanol and ether were distilled outunder reduced pressure. The resultant aqueous layer was adjusted to pH 4to 5, and extracted with ethyl acetate. After the separated organiclayer was dried with anhydrous magnesium sulfate, the solvent wasdistilled off to obtain{3(E)-(4'-carboxybutylidene)-6(S)-(3'(S)-hydroxy-3'-cyclopentyl-trans-1'-propenyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(32 mg, Yield: 74%) as colorless viscous liquid. The product solidifiedwhen allowed to stand.

IR (neat): 3400, 1710 cm⁻¹.

NMR δ (CDCl₃): 5.54 (m, 2H), 5.24 (t, J=7 Hz, 1H), 3.50-4.00 (m, 2H).

Mass m/z: 348, 330, 312.

The thus obtained product is a carbacyclin analog. The usefulnessthereof was published in '83 Inflammation Seminar--Prostaglandin ProgramPreliminary Text, p. 37, (Ono-Yakuhin-Kogyo-KK., Central ResearchCenter, Akiyoshi Kawasaki).

REFERENCE EXAMPLE 66

The reaction was carried out following the same procedures as inReference example 65 by using{3(E)-(4'-ethoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-3'(S)-hydroxy-3'-cyclopentyl-trans-1'-propeneyl-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(45 mg, 0.12 mmol) to obtain{3(E)-(4'-carboxylbutylidene)-6(S)-(3'(S)-hydroxy-3'(S)-cyclopentyl-trans-1'-propenyl-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(33 mg, Yield: 80%) as white solid product. Each spectrum data thereofaccorded with those obtained in Reference example 65.

REFERENCE EXAMPLE 67

The reaction was carried out following the same procedures as inReference example 65 by using{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(45 mg, 0.12 mmol) to obtain{3(E)-(4'-carboxylbutylidene)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(35 mg, Yield: 80%) as viscous colorless oily product. Each spectrumdata thereof accorded with those obtained in Reference example 52.

REFERENCE EXAMPLE 68

The reaction was carried out following the same procedures as inReference example 65 by using{3(E)-(4'-ethoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(47 mg, 0.12 mmol) to obtain{3(E)-(4'-carboxylbutylidene)-6(S)-(3'(S)-hydroxy-4'(RS)-methyl-trans-1'-octen-6'-ynyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(35 mg, Yield: 80%) as viscous colorless oily product. Each spectrumdata thereof accorded with those obtained in Reference example 67.

REFERENCE EXAMPLE 69

The reaction was carried out following the same procedures as inReference example 65 by using{3(E)-(4'-methoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(50 mg, 0.12 mmol) to obtain{3(E)-(4'-carboxylbutylidene)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(39 mg, Yield: 80%) as viscous colorless oily products. Each spectrumdata thereof accorded with those obtained in Reference example 53.

REFERENCE EXAMPLE 70

The reaction was carried out following the same procedures as inReference example 67 by using{3(E)-(4'-ethoxycarbonylbutylidene)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(50 mg, 0.12 mmol) to obtain{3(E)-(4'-carboxybutylidene)-6(S)-(3'(S)-hydroxy-5'(R)-methyl-9'-methyl-trans-1'-decene-8'-enyl)-7(R)-hydroxy-(1S,5S)-cis-bicyclo[3.3.0]octane}(39 mg, Yield: 80%) as viscous colorless oily product. Each spectrumdata thereof accorded with those obtained in Reference example 69.

TEST EXAMPLE 1

In the compounds synthsized by the method as described above,9(0)-methano-Δ⁶(9α) -PGI₁, for example, has a biological activity asmentioned below. When the rabbit serum was employed, it depressd acohesion of platelets to be induced by adenosine diphosphate (ADP) at apotency of 1/10 to that of PGI₂, and it showed a potency of 1/2 to thatof PGI₂ when the human blood was employed. As for the effects to theblood pressure, when rat was examined, it showed the same effect as thatof PGI₂ and showed blood pressure depressing action at a dosage of 0.1μg/kg. An effect to the heart stroke frequencies thereof are almost thesame as that of PGI₂, and increasing of the heart stroke frequencieswere obserbed at a dosage of 1 μg/kg thereof in an experiment by usingrats. As for an anti-fester action, it showed an activity at a lowconcentration of 10⁻⁶ M in an experiment by using rabbit stomach, and itwas the same strength as that of PGE.sub. 2. Cytotoxicity thereof areextremely weak and IC₅₀ =5 μg/ml.

We claim:
 1. A bicyclo[3.3.0]octenylaldehyde derivative represented bythe formula: ##STR39## wherein R¹ is a substituent selected from thegroup consisting of a hydrogen atom and a protective group of a hydroxygroup;R² is a substituent selected from the group consisting of --CH₂OR⁵, ##STR40## where R⁵ is a substituent selected from the groupconsisting of a hydrogen atom and a protective group of a hydroxy group,R⁶ is a substituent selected from the group consisting of an alkylgroup, an alkenyl group and an alkynyl group, said substituent beingstraight, branched or cyclic and having 5 to 10 carbon atoms, X is asubstituent selected from the group consisting of a vinylene group andan acetylene group, and R⁷ is a substituent selected from the groupconsisting of an alkyl group, an alkenyl group, and an alkynyl groupsaid substituent being straight, branched or cyclic and having 5 to 10carbon atoms; and R⁴ is a hydrogen atom.
 2. Thebicyclo[3.3.0]octenylaldehyde derivative according to claim 1, whereinsaid derivative is represented by the formula: ##STR41## wherein R¹ andR⁵ have the same meaning as defined in claim 1.